Inhibitors of Histone Deacetylase

ABSTRACT

The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 11/090,713,filed Mar. 25, 2005, which claims priority from U.S. ProvisionalApplication Ser. No. 60/556,828, filed Mar. 26, 2004, which areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the inhibition of histone deacetylase. Moreparticularly, the invention relates to compounds and methods forinhibiting histone deacetylase enzymatic activity.

2. Summary of the Related Art

In eukaryotic cells, nuclear DNA associates with histones to form acompact complex called chromatin. The histones constitute a family ofbasic proteins which are generally highly conserved across eukaryoticspecies. The core histones, termed H2A, H2B, H3, and H4, associate toform a protein core. DNA winds around this protein core, with the basicamino acids of the histones interacting with the negatively chargedphosphate groups of the DNA. Approximately 146 base pairs of DNA wraparound a histone core to make up a nucleosome particle, the repeatingstructural motif of chromatin.

Csordas, Biochem. J., 286: 23-38 (1990) teaches that histones aresubject to posttranslational acetylation of the ε-amino groups ofN-terminal lysine residues, a reaction that is catalyzed by histoneacetyl transferase (HAT1). Acetylation neutralizes the positive chargeof the lysine side chain, and is thought to impact chromatin structure.Indeed, Taunton et al., Science, 272: 408-411 (1996), teaches thataccess of transcription factors to chromatin templates is enhanced byhistone hyperacetylation. Taunton et al. further teaches that anenrichment in underacetylated histone H4 has been found intranscriptionally silent regions of the genome.

Histone acetylation is a reversible modification, with deacetylationbeing catalyzed by a family of enzymes termed histone deacetylases(HDACs). The molecular cloning of gene sequences encoding proteins withHDAC activity has established the existence of a set of discrete HDACenzyme isoforms. Grozinger et al., Proc. Natl. Acad. Sci. USA, 96:4868-4873 (1999), teaches that HDACs is divided into two classes, thefirst represented by yeast Rpd3-like proteins, and the secondrepresented by yeast Hda1-like proteins. Grozinger et al. also teachesthat the human HDAC1, HDAC2, and HDAC3 proteins are members of the firstclass of HDACs, and discloses new proteins, named HDAC4, HDAC5, andHDAC6, which are members of the second class of HDACs. Kao et al., Genes& Dev., 14: 55-66 (2000), discloses HDAC7, a new member of the secondclass of HDACs. Van den Wyngaert, FEBS, 478: 77-83 (2000) disclosesHDAC8, a new member of the first class of HDACs. Zhou, X. et al., Proc.Natl. Acad. Sci. U.S.A. 98 (19), 10572-10577 (2001) discloses cloningand characterization of HDAC9. Kao, H. Y. et al., J. Biol. Chem. 277(1), 187-193 (2002) discloses isolation and characterization ofmammalian HDAC10. Gao L. et al., J Biol Chem. 277(28): 25748-55 (2002)discloses cloning and functional characterization of HDAC11.

Richon et al., Proc. Natl. Acad. Sci. USA, 95: 3003-3007 (1998),discloses that HDAC activity is inhibited by trichostatin A (TSA), anatural product isolated from Streptomyces hygroscopicus, and by asynthetic compound, suberoylanilide hydroxamic acid (SAHA). Yoshida andBeppu, Exper. Cell Res., 177: 122-131 (1988), teaches that TSA causesarrest of rat fibroblasts at the G₁ and G₂ phases of the cell cycle,implicating HDAC in cell cycle regulation. Indeed, Finnin et al.,Nature, 401: 188-193 (1999), teaches that TSA and SAHA inhibit cellgrowth, induce terminal differentiation, and prevent the formation oftumors in mice. Suzuki et al., U.S. Pat. No. 6,174,905, EP 0847992, JP258863/96, and Japanese Application No. 10138957, disclose benzamidederivatives that induce cell differentiation and inhibit HDAC. Delormeet al., WO 01/38322 and PCT IB01/00683, disclose additional compoundsthat serve as HDAC inhibitors.

These findings suggest that inhibition of HDAC activity represents anovel approach for intervening in cell cycle regulation and that HDACinhibitors have great therapeutic potential in the treatment of cellproliferative diseases or conditions. To date, few inhibitors of histonedeacetylase are known in the art. There is thus a need to identifyadditional HDAC inhibitors and to identify the structural featuresrequired for potent HDAC inhibitory activity.

BRIEF SUMMARY OF THE INVENTION

The invention provides compounds and methods for treating cellproliferative diseases. The invention provides new inhibitors of histonedeacetylase enzymatic activity.

In a first aspect, the invention provides compounds that are useful asinhibitors of histone deacetylase.

In a second aspect, the invention provides a composition comprising aninhibitor of histone deacetylase according to the invention and apharmaceutically acceptable carrier, excipient, or diluent.

In a third aspect, the invention provides a method of inhibiting histonedeacetylase in a cell, comprising contacting a cell in which inhibitionof histone deacetylase is desired with an inhibitor of histonedeacetylase of the invention.

In a fourth aspect, the invention provides a method for treating cellproliferative diseases.

The foregoing merely summarizes certain aspects of the invention and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides compounds and methods for inhibiting histonedeacetylase enzymatic activity. The invention also provides compositionsand methods for treating cell proliferative diseases and conditions. Thepatent and scientific literature referred to herein establishesknowledge that is available to those with skill in the art. The issuedpatents, applications, and references that are cited herein are herebyincorporated by reference to the same extent as if each was specificallyand individually indicated to be incorporated by reference. In the caseof inconsistencies, the present disclosure will prevail.

For purposes of the present invention, the following definitions will beused (unless expressly stated otherwise):

As used herein, the terms “histone deacetylase” and “HDAC” are intendedto refer to any one of a family of enzymes that remove acetyl groupsfrom the ε-amino groups of lysine residues at the N-terminus of ahistone. Unless otherwise indicated by context, the term “histone” ismeant to refer to any histone protein, including H1, H2A, H2B, H3, H4,and H5, from any species. Preferred histone deacetylases include class Iand class II enzymes. Preferably the histone deacetylase is a humanHDAC, including, but not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4,HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-10, and HDAC-11. In someother preferred embodiments, the histone deacetylase is derived from aprotozoal or fungal source.

The terms “histone deacetylase inhibitor” and “inhibitor of histonedeacetylase” are used to identify a compound having a structure asdefined herein, which is capable of interacting with a histonedeacetylase and inhibiting its enzymatic activity. “Inhibiting histonedeacetylase enzymatic activity” means reducing the ability of a histonedeacetylase to remove an acetyl group from a histone. In some preferredembodiments, such reduction of histone deacetylase activity is at leastabout 50%, more preferably at least about 75%, and still more preferablyat least about 90%. In other preferred embodiments, histone deacetylaseactivity is reduced by at least 95% and more preferably by at least 99%.

Preferably, such inhibition is specific, i.e., the histone deacetylaseinhibitor reduces the ability of a histone deacetylase to remove anacetyl group from a histone at a concentration that is lower than theconcentration of the inhibitor that is required to produce another,unrelated biological effect. Preferably, the concentration of theinhibitor required for histone deacetylase inhibitory activity is atleast 2-fold lower, more preferably at least 5-fold lower, even morepreferably at least 10-fold lower, and most preferably at least 20-foldlower than the concentration required to produce an unrelated biologicaleffect.

For simplicity, chemical moieties are defined and referred to throughoutprimarily as univalent chemical moieties (e.g., alkyl, aryl, etc.).Nevertheless, such terms are also used to convey correspondingmultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, while an “alkyl” moietygenerally refers to a monovalent radical (e.g. CH₃—CH₂—), in certaincircumstances a bivalent linking moiety can be “alkyl,” in which casethose skilled in the art will understand the alkyl to be a divalentradical (e.g., —CH₂—CH₂—), which is equivalent to the term “alkylene.”(Similarly, in circumstances in which a divalent moiety is required andis stated as being “aryl,” those skilled in the art will understand thatthe term “aryl” refers to the corresponding divalent moiety, arylene.)All atoms are understood to have their normal number of valences forbond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 forS, depending on the oxidation state of the S). On occasion a moiety maybe defined, for example, as (A)_(a)-B—, wherein a is 0 or 1. In suchinstances, when a is 0 the moiety is B— and when a is 1 the moiety isA-B—.

The term “hydrocarbyl” refers to a straight, branched, or cyclic alkyl,alkenyl, or alkynyl, each as defined herein. A “C₀” hydrocarbyl is usedto refer to a covalent bond. Thus, “C₀-C₃-hydrocarbyl” includes acovalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl,propynyl, and cyclopropyl.

The term “alkyl” as employed herein refers to straight and branchedchain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8carbon atoms, and more preferably 1-6 carbon atoms, which is optionallysubstituted with one, two or three substituents. Preferred alkyl groupsinclude, without limitation, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. A “C₀” alkyl (as in“C₀-C₃-alkyl”) is a covalent bond (like “C₀” hydrocarbyl).

The term “alkenyl” as used herein means an unsaturated straight orbranched chain aliphatic group with one or more carbon-carbon doublebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms, which is optionally substitutedwith one, two or three substituents. Preferred alkenyl groups include,without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term “alkynyl” as used herein means an unsaturated straight orbranched chain aliphatic group with one or more carbon-carbon triplebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms, which is optionally substitutedwith one, two or three substituents. Preferred alkynyl groups include,without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

An “alkylene,” “alkenylene,” or “alkynylene” group is an alkyl, alkenyl,or alkynyl group, as defined hereinabove, that is positioned between andserves to connect two other chemical groups. Preferred alkylene groupsinclude, without limitation, methylene, ethylene, propylene, andbutylene. Preferred alkenylene groups include, without limitation,ethenylene, propenylene, and butenylene. Preferred alkynylene groupsinclude, without limitation, ethynylene, propynylene, and butynylene.

The term “cycloalkyl” as employed herein includes saturated andpartially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons,preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, whereinthe cycloalkyl group additionally is optionally substituted. Preferredcycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl.

The term “heteroalkyl” refers to an alkyl group, as defined hereinabove,wherein one or more carbon atoms in the chain are replaced by aheteroatom selected from the group consisting of O, S, and N.

An “aryl” group is a C₆-C₁₄ aromatic moiety comprising one to threearomatic rings, which is optionally substituted. Preferably, the arylgroup is a C₆-C₁₀ aryl group. Preferred aryl groups include, withoutlimitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An “aralkyl”or “arylalkyl” group comprises an aryl group covalently linked to analkyl group, either of which may independently be optionally substitutedor unsubstituted. Preferably, the aralkyl group is(C₁-C₆)alk(C₆-C₁₀)aryl, including, without limitation, benzyl,phenethyl, and naphthylmethyl.

A “heterocyclic” group (or “heterocyclyl) is an optionally substitutednonaromatic mono-, bi-, or tricyclic structure having from about 3 toabout 14 atoms, wherein one or more atoms are selected from the groupconsisting of N, O, and S. One ring of a bicyclic heterocycle or tworings of a tricyclic heterocycle may be aromatic, as in indan and9,10-dihydro anthracene. The heterocyclic group is optionallysubstituted on carbon with oxo or with one of the substituents listedabove. The heterocyclic group may also independently be substituted onnitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl,arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or onsulfur with oxo or lower alkyl. Preferred heterocyclic groups include,without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl,piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl,and morpholino. In certain preferred embodiments, the heterocyclic groupis fused to an aryl, heteroaryl, or cycloalkyl group. Examples of suchfused heterocycles include, without limitation, tetrahydroquinoline anddihydrobenzofuran. Specifically excluded from the scope of this term arecompounds where an annular O or S atom is adjacent to another O or Satom.

As used herein, the term “heteroaryl” refers to optionally substitutedgroups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms;having 6, 10, or 14 pi electrons shared in a cyclic array; and having,in addition to carbon atoms, between one or more heteroatoms selectedfrom the group consisting of N, O, and S. For example, a heteroarylgroup may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl,benzothiazolyl, benzofuranyl and indolinyl. Preferred heteroaryl groupsinclude, without limitation, thienyl, benzothienyl, furyl, benzofuryl,dibenzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl,oxazolyl, thiazolyl, triazolyl, and isoxazolyl.

A “heteroaralkyl” or “heteroarylalkyl” group comprises a heteroarylgroup covalently linked to an alkyl group, either of which isindependently optionally substituted or unsubstituted. Preferredheteroalkyl groups comprise a C₁-C₆ alkyl group and a heteroaryl grouphaving 5, 6, 9, or 10 ring atoms. Specifically excluded from the scopeof this term are compounds having adjacent annular O and/or S atoms.Examples of preferred heteroaralkyl groups include pyridylmethyl,pyridylethyl, pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl,imidazolylethyl, thiazolylmethyl, and thiazolylethyl.

An “arylene,” “heteroarylene,” or “heterocyclylene” group is an aryl,heteroaryl, or heterocyclyl group, as defined hereinabove, that ispositioned between and serves to connect two other chemical groups.

Preferred heterocyclyls and heteroaryls include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

As employed herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl,heteroaryl, heterocyclic, urea, etc.) is described as “optionallysubstituted” it is meant that the group optionally has from one to four,preferably from one to three, more preferably one or two, non-hydrogensubstituents. Suitable substituents include, without limitation, halo,hydroxy, oxo (e.g., an annular —CH— substituted with oxo is —C(O)—)nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, haloalkoxy,aryloxy, heteroaryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl,aminoalkyl, acyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl,sulfonamido, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido,alkylcarbonyl, acyloxy, cyano, alkylthio, ureido, and ureidoalkylgroups. Preferred substituents, which are themselves not furthersubstituted (unless expressly stated otherwise) are:

-   -   (a) halo, cyano, oxo, alkyl, alkoxy, alkylthio, haloalkoxy,        aminoalkyl, aminoalkoxy, carboxy, formyl, nitro, amino, amidino,        carbamoyl, guanidino, C₃-C₇ heterocycle, heterocyclylalkyl,        heterocyclylcarbonyl, hydroxyalkyl, alkoxyalkyl,    -   (b) C₁-C₅ alkyl or alkenyl or arylalkyl imino, carbamoyl,        carbamate, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl,        alkylaryl, arylalkyl, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkoxy,        C₁-C₈ alkoxycarbonyl, aryloxycarbonyl, C₂-C₈ acyl, C₂-C₈        acylamino, C₁-C₈ alkylthio, arylalkylthio, arylthio,        heteroarylthio, C₁-C₈ alkylsulfinyl, arylalkylsulfinyl,        arylsulfinyl, C₁-C₈ alkylsulfonyl, arylalkylsulfonyl,        arylsulfonyl, C₀-C₆ N-alkyl carbamoyl, C₂-C₁₅        N,N-dialkylcarbamoyl, C₃-C₇ cycloalkyl, aroyl, aryloxy,        heteroaryloxy, arylalkyl ether, C₃-C₇ heterocyclylalkylether,        aryl, aryl fused to a cycloalkyl or heterocycle or another aryl        ring, C₃-C₇ heterocycle, heteroaryl, arylcarbamoyl, or any of        these rings fused or spiro-fused to a cycloalkyl, heterocyclyl,        or aryl, wherein any of the foregoing which are additionally        substitutable is further optionally substituted with one more        moieties listed in (a), above; and    -   (c) —(CH₂)_(s)—NR³⁰R³¹, wherein s is from 0 (in which case the        nitrogen is directly bonded to the moiety that is substituted)        to 6, and R³⁰ and R³¹ are each independently hydrogen, cyano,        oxo, carboxamido, amidino, C₁-C₈ hydroxyalkyl, C₁-C₃ alkylaryl,        aryl-C₁-C₃ alkyl, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkoxy,        C₁-C₈ alkoxycarbonyl, aryloxycarbonyl, aryl-C₁-C₃        alkoxycarbonyl, C₂-C₈ acyl, C₁-C₈ alkylsulfonyl,        arylalkylsulfonyl, arylsulfonyl, aroyl, aryl, cycloalkyl,        heterocyclyl, or heteroaryl, wherein each of the foregoing is        further optionally substituted with one more moieties listed in        (a), above; or    -   R³⁰ and R³¹ taken together with the N to which they are attached        form a heterocyclyl or heteroaryl, each of which is optionally        substituted with from 1 to 3 substituents from (a), above.

In addition, substituents on cyclic moieties (i.e., cycloalkyl,heterocyclyl, aryl, heteroaryl) include 5-6 membered mono- and 9-14membered bi-cyclic moieties fused to the parent cyclic moiety to form abi- or tri-cyclic fused ring system. For example, an optionallysubstituted phenyl includes, but not limited to, the following:

Preferred substituents on cyclic moieties (i.e., cycloalkyl,heterocyclyl, aryl, heteroaryl) also include groups of the formula—K¹—N(H)(R¹⁰), wherein

-   -   K¹ is a chemical bond or C₁-C₄ alkylene;    -   R¹⁰ is selected from the group consisting of Z′ and -Ak²-Z′,        wherein    -   Ak² is C₁-C₄ alkylene; and    -   Z′ is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of        which optionally is substituted, and each of which optionally is        fused to one or more aryl or heteroaryl rings, or to one or more        saturated or partially unsaturated cycloalkyl or heterocyclic        rings.

Particularly preferred substituents on cyclic moieties (such as aryl,heteroaryl, cycloalkyl, heterocyclyl, or any of these rings fused to oneor more aryl or heteroaryl rings, or to one or more saturated orpartially unsaturated cycloalkyl or heterocyclic rings), include 1, 2,or 3 groups independently selected from the following:

-   -   a) alkoxy, cyano, amino, oxo, haloalkyl, halo, alkyl,        R₅₀—C(O)—N(R₃₂)—, R₅₀—O—C(O)—N(R₃₂)—, R₅₀—NH—C(O)—N(R₃₂)—,        R₅₀—NH—C(O)—O—, (R₃₂)(R₃₃)N-alkyl-, (R₃₂)(R₃₃)N-alkyl-O—,        (R₃₂)(R₃₃)N-alkenylene-N(R₃₂)—,        N(R₃₂)-aryl-N(R₃₂)—C(O)-arylalkyl-N(R₃₂)—;        -   wherein R₅₀ is cycloakyl, heterocyclyl-C₁-C₆ alkyl-,            R₃₂R₃₃N-alkyl-, or alkyl;    -   b) aryl-C₀-C₆ alkyl-, heteroaryl-C₀-C₆ alkyl-, cycloalkyl-C₀-C₆        alkyl-, heterocyclyl-C₀-C₆ alkyl-, aryl-C₀-C₆ alkyl-N(R₃₂)—,        aryl-C(O)—, heteroaryl-C₀-C₆ alkyl-N(R₃₂)—, heterocyclyl-C₀-C₆        alkyl-N(R₃₂)—, aryl-O—, heteroaryl-O—, aryl-S—, heteroaryl-S—,        aryl-SO₂—, heteroaryl-SO₂, aryl-C(O)N(R₃₂)—,        heteroaryl-C(O)N(R₃₂)—, heteroaryl-C(H)(SO₂-heteroaryl)-N(R₃₂)—;    -   wherein R₃₂ and R₃₃ are independently H or C₁-C₆ alkyl, or R₃₂        and R₃₃ taken together with the N to which they are attached        form a heterocyclyl or heteroaryl;    -   and wherein any of the rings described in paragraphs        [0045]-[0048] are further optionally substituted with 1, 2, or 3        groups independently selected from alkyl, alkoxy, thioalkoxy,        alkyl-SO₂—, amino, halo, cyano, haloalkyl, hydroxyalkyl,        alkoxyalkoxyalkyl, COOH, alkanoyl, alkanoate, NO₂, hydroxy,        haloalkoxy, (R₃₂)(R₃₃)N—C₀-C₆ alkyl-, (R₃₂)(R₃₃)N—C₀-C₆        alkyl-O—, (R₃₂)(R₃₃)N—C(O)—, heteroaryl, alkyl-C(O)N(R₃₂)—,        aryl-O—, (R₃₂)(R₃₃)N—SO₂—, aryl, and        (R₃₂)(R₃₃)N—alkyl-C(O)N(R₃₂)—.

A “halohydrocarbyl” is a hydrocarbyl moiety in which from one to allhydrogens have been replaced with one or more halo.

The term “halogen” or “halo” as employed herein refers to chlorine,bromine, fluorine, or iodine. As herein employed, the term “acyl” refersto an alkylcarbonyl or arylcarbonyl substituent. The term “acylamino”refers to an amide group attached at the nitrogen atom (i.e., R—CO—NH—).The term “carbamoyl” refers to an amide group attached at the carbonylcarbon atom (i.e., NH₂—CO—). The nitrogen atom of an acylamino orcarbamoyl substituent is additionally optionally substituted. The term“sulfonamido” refers to a sulfonamide substituent attached by either thesulfur or the nitrogen atom. The term “amino” is meant to include NH₂,alkylamino, arylamino, and cyclic amino groups. The term “ureido” asemployed herein refers to a substituted or unsubstituted urea moiety.

The term “radical” as used herein means a chemical moiety comprising oneor more unpaired electrons.

A moiety that is substituted is one in which one or more hydrogens havebeen independently replaced with another chemical substituent. As anon-limiting example, substituted phenyls include 2-flurophenyl,3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluoro-3-propylphenyl.As another non-limiting example, substituted N-octyls include2,4dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included within thisdefinition are methylenes (—CH₂—) substituted with oxygen to formcarbonyl —CO—).

An “unsubstituted” moiety as defined above (e.g., unsubstitutedcycloalkyl, unsubstituted heteroaryl, etc.) means that moiety as definedabove that does not have any of the optional substituents for which thedefinition of the moiety (above) otherwise provides. Thus, for example,while an “aryl” includes phenyl and phenyl substituted with a halo,“unsubstituted aryl” does not include phenyl substituted with a halo.

Throughout the specification preferred embodiments of one or morechemical substituents are identified. Also preferred are combinations ofpreferred embodiments. For example, paragraph [0080] describes preferredembodiments of Cy in the compound of formula (1a) and paragraph [0078]describes preferred embodiments of W of the compound of formula (1a).Thus, also contemplated as within the scope of the invention arecompounds of formula (1) in which Cy is as described in paragraph [0080]and W is as described in paragraph [0078].

Some compounds of the invention may have chiral centers and/or geometricisomeric centers (E- and Z-isomers), and it is to be understood that theinvention encompasses all such optical, diastereoisomers and geometricisomers. The invention also comprises all tautomeric forms of thecompounds disclosed herein. Where compounds of the invention includechiral centers, the invention encompasses the enantiomerically pureisomers of such compounds, the enantiomerically enriched mixtures ofsuch compounds, and the racemic mixtures of such compounds.

The compounds of the invention may be administered in the form of an invivo hydrolyzable ester or in vivo hydrolyzable amide. An in vivohydrolyzable ester of a compound of the invention containing carboxy orhydroxy group is, for example, a pharmaceutically acceptable ester whichis hydrolyzed in the human or animal body to produce the parent acid oralcohol. Suitable pharmaceutically acceptable esters for carboxy includeC₁₋₆-alkoxymethyl esters (e.g., methoxymethyl), C₁₋₆-alkanoyloxymethylesters (e.g., for example pivaloyloxymethyl), phthalidyl esters,C₃₋₈-cycloalkoxycarbonyloxyC₁₋₆-alkyl esters (e.g.,1-cyclohexylcarbonyloxyethyl); 1,3-dioxolen-2-onylmethyl esters (e.g.,5-methyl-1,3-dioxolen-2-onylmethyl; and C₁₋₆-alkoxycarbonyloxyethylesters (e.g., 1-methoxycarbonyloxyethyl) and may be formed at anycarboxy group in the compounds of this invention.

An in vivo hydrolyzable ester of a compound of the invention containinga hydroxy group includes inorganic esters such as phosphate esters anda-acyloxyalkyl ethers and related compounds which as a result of the invivo hydrolysis of the ester breakdown to give the parent hydroxy group.Examples of α-acyloxyalkyl ethers include acetoxymethoxy and2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolyzableester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyland substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkylcarbonate esters), dialkylcarbamoyl andN—(N,N-dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),N,N-dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.A suitable value for an in vivo hydrolyzable amide of a compound of theinvention containing a carboxy group is, for example, a N—C₁₋₆-alkyl orN,N-di-C₁₋₆-alkyl amide such as N-methyl, N-ethyl, N-propyl,N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.

Compounds

In a first aspect, the invention provides novel inhibitors of histonedeacetylase. In a first embodiment, the novel inhibitors of histonedeacetylase are represented by formula (1):

and pharmaceutically acceptable salts thereof, wherein

X is selected from the group consisting of a chemical bond, L, W-L, L-W,L-W-L, and L-W′-L-W′, wherein

-   -   Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of        which is optionally substituted and each of which is optionally        fused to one or more aryl or heteroaryl rings, or to one or more        saturated or partially unsaturated cycloalkyl or heterocyclic        rings, each of which rings is optionally substituted;    -   W, at each occurrence, is S, O, C═O, —NH—C(═O)—NH—, —NHSO₂—, or        N(R⁹), where R⁹ is selected from the group consisting of        hydrogen, alkyl, hydroxyalkyl, and t-butoxycarbonyl;

W′ at each occurrence is independently a chemical bond, S, O, or NH; and

-   -   L, at each occurrence, is independently a chemical bond or C₁-C₄        alkylene; or    -   Ar is arylene or heteroarylene, each of which is optionally        substituted;    -   q is 0 or 1; and    -   T is NH₂ or OH;    -   provided that when Cy is naphthyl, X is —CH₂—, Ar is phenyl, and        q is 0 or 1, T is not OH.

In some preferred embodiments of the compound according to paragraph[0059], q is 1, and T is NH₂.

Preferred compounds of the embodiments of paragraph [0070] include thosewherein Ar is phenylene, and Cy-X— is

In some preferred embodiments of the compounds according to paragraph[0059], q is 0.

In a preferred embodiment, the HDAC inhibitors of the invention comprisecompounds of paragraph [0072] having formula (1a):

and pharmaceutically acceptable salts thereof, wherein

-   -   Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of        which is optionally substituted and each of which is optionally        fused to one or more aryl or heteroaryl rings, or to one or more        saturated or partially unsaturated cycloalkyl or heterocyclic        rings, each of which rings is optionally substituted;    -   W is S, O, or N(R₉), wherein R₉ is hydrogen or C₁-C₆-alkyl;    -   R₈ is H or C₁-C₄ alkyl; and    -   T is NH₂ or OH.

In some preferred embodiments of the compounds according to paragraph[0073], W is NH or S.

Preferred compounds according to the invention, and particularlyparagraph [0078], include those wherein Cy is selected from phenyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, benzothiazolyl,benzoimidazolyl, and benzotriazolyl, each of which is optionallysubstituted.

Preferred compounds according to paragraph [0080] include those of thestructure 1a-1:

and pharmaceutically acceptable salts thereof, wherein W is NH or S; P,Q, M, G and U are independently CH or N, provided that no more than twoof P, Q, M, G and U are N and in the ring containing P, Q, M, G, and U,an annular S or O is not adjacent to another annular S or O; R₈ is H orC₁-C₄ alkyl; and A and B are as defined below.

Preferred compounds according to paragraph [0080] include those of thestructure 1a-2:

and pharmaceutically acceptable salts thereof, wherein W is S or NH; R₈is H or C₁-C₄ alkyl; and A and B are as defined below.

Preferred compounds according to paragraph [0080] include those of thestructure 1a-3:

and pharmaceutically acceptable salts thereof, wherein W is S or NH, andA and B are as defined below.

Preferred compounds according to paragraph [0085] include those whereinW is NH.

Preferred compounds according to paragraph [0080] include those of thestructure 1a-4:

and pharmaceutically acceptable salts thereof, wherein W is S or NH; Dis N—R₁₀ or S, E is N or C-A; R₈ and R₁₀ are independently H or C₁-C₄alkyl; and A and B are as described below.

Preferred compounds according to paragraph [0088] include those whereinW is NH.

Preferred compounds according to paragraph [0081] include those of theformula 1a-5:

and pharmaceutically acceptable salts thereof.

Preferred compounds according to paragraph [0091] include those whereinW is NH.

Preferred compounds according to paragraphs [0073] and [0078] alsoinclude those wherein W is NH and Cy is quinoxalinyl, phthalimidyl, orbenzodioxolyl, each of which is optionally substituted with A and/or B,wherein A and B are as defined below.

In a further preferred embodiment, the HDAC inhibitors of the inventioncomprise compounds of paragraph [0059] having formula (1b):

(1b)

and pharmaceutically acceptable salts thereof, wherein

-   -   Cy is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of        which is optionally substituted and each of which is optionally        fused to one or more aryl or heteroaryl rings, or to one or more        saturated or partially unsaturated cycloalkyl or heterocyclic        rings, each of which rings is optionally substituted;    -   X is L, W-L, or L-W, wherein        -   W, at each occurrence, is S, O, or NH; and            -   L is —CH₂—;        -   Y is N or CH;        -   Z is O, S, NR₁₂ or CH₂;            -   R₁₂ is H or C₁-C₄ alkyl; and        -   T is NH₂ or OH.

In some preferred embodiments of the compounds according to paragraph[0095], T is NH₂.

Preferred compounds according to each of paragraphs [0095] and [0105]include those wherein X is —S—CH₂—, —NH—CH₂— or —CH₂—NH—.

Preferred compounds according to paragraphs [0095], [0105], and [0106]include those wherein Cy is aryl or heteroaryl, each of which isoptionally substituted.

Preferred compounds according to each of paragraphs [0095]-[0107]include those wherein Cy is phenyl, pyridyl, pyrimidinyl, orbenzothiazolyl, each of which is optionally substituted.

Preferred compounds according to each of paragraphs [0095]-[0108]include those wherein Cy is substituted with A and/or B, wherein A and Bare as defined in paragraph [0187].

Preferred compounds according to paragraph each of paragraphs[0095]-[0108] include those wherein Cy is optionally substituted withone two or three groups independently selected from alkoxy, acyl,morpholino, or phenyl optionally substituted with alkoxy.

In a further preferred embodiment, the HDAC inhibitors of the inventioncomprise compounds of paragraph [0059] having formula (1c):

and pharmaceutically acceptable salts thereof, wherein

-   -   Cy is aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of        which is optionally substituted and each of which is optionally        fused to one or more aryl or heteroaryl rings, or to one or more        saturated or partially unsaturated cycloalkyl or heterocyclic        rings, each of which rings is optionally substituted;    -   X is L, W-L, or L-W, wherein        -   W, at each occurrence, is S, O, or NH; and            -   L is —CH₂—;    -   Y is N or CH;    -   Z is O, S, NR₁₂ or CH₂;        -   R₁₂ is H or C₁-C₄ alkyl; and    -   T is NH₂ or OH.

In some preferred embodiments of the compounds according to paragraph[0111], T is NH₂.

Preferred compounds according to each of paragraphs [0111]-[0121]include those wherein X is —S—CH₂—, —NH—CH₂— or —CH₂—NH—.

Preferred compounds according to each of paragraphs [0111]-[0122]include those wherein Cy is aryl or heteroaryl, each of which isoptionally substituted.

Preferred compounds according to each of paragraphs [0111]-[0122]include those wherein Cy is phenyl, pyridyl, pyrimidinyl, orbenzothiazolyl, each of which is optionally substituted.

Preferred compounds according to each of paragraphs [0111]-[0124]include those wherein Cy is substituted with A and/or B, wherein A and Bare as defined in paragraph [0187].

Preferred compounds according to each of paragraphs [0111]-[0124]include those wherein Cy is optionally substituted with one two or threegroups independently selected from alkoxy, haloalkoxy, acyl, morpholino,or phenyl optionally substituted with alkoxy.

In a further preferred embodiment, the HDAC inhibitors of the inventioncomprise compounds of paragraph [0059] having formula (1d):

and pharmaceutically acceptable salts thereof, wherein

-   -   Cy is aryl, or heteroaryl, each of which is optionally        substituted and each of which is optionally fused to one or more        aryl or heteroaryl rings, or to one or more saturated or        partially unsaturated cycloalkyl or heterocyclic rings, each of        which rings is optionally substituted; and    -   T is NH₂ or OH.

In some preferred embodiments of the compounds according to paragraph[0127], T is NH₂.

Preferred compounds according to each of paragraphs [0127]-[0131]include those wherein Cy is optionally substituted heteroaryl oroptionally substituted heterocyclyl, each of which is optionally fusedto one or more aryl or heteroaryl rings, or to one or more saturated orpartially unsaturated cycloalkyl or heterocyclic rings, each of whichrings is optionally substituted.

Preferred compounds according to each of paragraphs [0127]-[0132]include those wherein Cy is:

In a further preferred embodiment, the HDAC inhibitors of the inventioncomprise compounds of paragraph [0059] having formula (1e):

and pharmaceutically acceptable salts thereof, wherein

-   -   Cy is aryl, heteroaryl, cycloalkyl, or heterocyclyl, each of        which is optionally substituted and each of which is optionally        fused to one or more aryl or heteroaryl rings, or to one or more        saturated or partially unsaturated cycloalkyl or heterocyclic        rings, each of which rings is optionally substituted; and    -   T is NH₂ or OH

In some preferred embodiments of the compounds according to paragraph[0134], T is NH₂.

Preferred compounds according to each of paragraphs [0134]-[0137]include those wherein Cy is heterocyclyl or heteroaryl, each of which isoptionally substituted, and each of which contains at least one nitrogenatom as part of the ring.

Preferred compounds according to each of paragraphs [0134]-[0139]include those wherein Cy is bound to phenyl through a nitrogen atom.

Preferred compounds according to each of paragraphs [0134]-[0139]include those wherein Cy is heterocyclyl, which is optionallysubstituted.

Preferred compounds according to paragraph each of paragraphs[0134]-[0139] and [0140] include those wherein Cy is piperidinyl, orpiperazinyl, each of which is optionally substituted.

Preferred compounds according to each of paragraphs [0134]-[0142]include those wherein Cy is optionally substituted with one or twosubstituents independently selected from A and B, wherein A and B are asdefined in paragraph [0187].

Preferred compounds according to each of paragraphs [0134]-[0142]include those wherein Cy is optionally substituted with one or twosubstituents independently selected from:

Preferred compounds according to paragraph [0072] include those whereinAr is phenylene, indolyl or indolinyl, each of which is optionallysubstituted, and X is absent, CH₂, —O—CH₂—, —S—CH₂—, —S—C(CH₃)(H)—, or—N(R₉)—CH₂—

Preferred compounds according to paragraph [0145] include those whereinAr is an indolyl or indolinyl group, X is CH₂ or —N(R₉)—CH₂—, and Cy is:

Preferred compounds according to paragraph [0145] include those whereinAr is phenylene, X is —S—CH₂—, or —S—C(CH₃)(H)—, and Cy is:

wherein Y is selected from:

Preferred compounds according to paragraph 0 include those wherein Y′ isH, and Y″ is:

Preferred compounds according to paragraph [0145] include those of theformula (1f):

Preferred compounds according to paragraph [0150] include those whereinCy is heterocyclyl or heteroaryl, each of which is optionallysubstituted, and each of which contains at least one nitrogen atom aspart of the ring.

Preferred compounds according to paragraph [0151] include those whereinCy is bound to the phenyl through a nitrogen atom.

Preferred compounds according to paragraph [0150] include those whereinCy is:

Preferred compounds according to paragraph [0150] include those of theformula (1f-1):

and pharmaceutically acceptable salts thereof, wherein T is OH or NH₂and A is as defined below.

Preferred compounds according to paragraph [0154] include those whereinT is NH₂.

Preferred compounds according to paragraph [0145] include those whereinAr is phenylene, X is —O—CH₂—, and Cy is:

In a further preferred embodiment, the HDAC inhibitors of the inventioncomprise compounds of paragraph [0059] having formula (1 g):

and pharmaceutically acceptable salts thereof, wherein

-   -   Cy is aryl, or heteroaryl, cycloalkyl, or heterocyclyl, each of        which is optionally substituted and each of which is optionally        fused to one or more aryl or heteroaryl rings, or to one or more        saturated or partially unsaturated cycloalkyl or heterocyclic        rings, each of which rings is optionally substituted;    -   X is L, W-L, or L-W, wherein        -   W, at each occurrence, is S, O, or NH; and            -   L is —CH₂—;    -   T is NH₂ or OH.

Preferred compounds according to paragraph [0158] include those whereinCy is optionally substituted heteroaryl. More preferably, Cy isoptionally substituted pyrimidinyl. Also preferably, Cy is pyrimidinylsubstituted with pyridyl.

Preferred compounds according to paragraph [0158] also include thosewherein X is —NH—CH₂—.

Preferred compounds according to paragraph [0158] also include compoundswherein T is NH₂.

Preferred compounds according to paragraph [0059] include those of theformula (1 h):

and pharmaceutically acceptable salts thereof, where W is S, O, or NHand A and B are as described below.

Preferred compounds according to paragraph [0167] include those whereinW is NH.

Preferred compounds according to paragraph [0167] include those whereinA is optionally substituted pyridyl or optionally substituted phenyl.

Preferred compounds according to paragraph [0167] include those whereinB is H or halo. Preferably, halo is chloro.

Preferred compounds according to paragraph [0059] include those of theformula (1i):

and pharmaceutically acceptable salts thereof, where W is S, O, or NHand R₄₀ is H or C₁-C₆ alkyl.

Preferred compounds according to paragraph [0173] include those whereinW is NH.

Preferred compounds according to paragraph [0173] include those whereinR₄₀ is H.

Preferred compounds according to paragraph [0173] include those whereinR₄₀ is methyl.

In a further preferred embodiment, the novel histone deacetylaseinhibitors of the invention are compounds of formula (2)

and pharmaceutically acceptable salts thereof, wherein

Cy² is aryl or heteroaryl, each of which is optionally substituted andwherein each of aryl, and heteroaryl is optionally fused to one or morearyl or heteroaryl rings, or to one or more saturated or partiallyunsaturated cycloalkyl or heterocyclic rings, each of which rings isoptionally substituted;

X is selected from the group consisting of: a covalent bond,C₀-C₄-hydrocarbyl, C₀-C₄-hydrocarbyl-(CO)—C₀-C₄-hydrocarbyl,C₀-C₄-hydrocarbyl-(NR⁷)—C₀-C₄-hydrocarbyl,C₀-C₄-hydrocarbyl-(S)—C₀-C₄-hydrocarbyl,C₀-C₄-hydrocarbyl-(O)—C₀-C₄-hydrocarbyl,C₀-C₄-hydrocarbyl-(SO)—C₀-C₄-hydrocarbyl, C₀-C₄-hydrocarbyl—(SO₂)—C₀-C₄-hydrocarbyl, C₀-C₄-hydrocarbyl—(NH)—(CO)—C₀-C₄-hydrocarbyl, C₀-C₄-hydrocarbyl—(CO)—(NH)—C₀-C₄-hydrocarbyl, —NH—CO—NH—, —NH—CS—NH—, —O—CO—O—,—O—CS—O—, —NH—C(NH)—NH—, —S(O)₂—N(R⁷)—, —N(R⁷)—S(O)₂—, —NH—C(O)—O—, and—O—C(O)—NH—,

-   -   wherein R⁷ is selected from the group consisting of hydrogen,        C₁-C₅-alkyl, aryl, aralkyl, acyl, heterocyclyl, heteroaryl,        SO₂-alkyl, SO₂-aryl, CO-alkyl, CO-aryl, CO—NH-alkyl, CO—NH-aryl,        CO—O-alkyl and CO—O-aryl, each of which is optionally        substituted,

n is 0 to 4,

Y is N or CH,

T is NH₂ or OH.

Compounds of formula (2) contain a chiral center (indicated by theasterisk (*)). The invention encompasses both racemic mixtures andenantiomerically enriched mixtures of compounds of formula (2), as wellas the enantiomerically pure isomers of compounds of formula (2).Preferably in enantiomerically enriched mixtures there is greater orequal to 80% of one enantiomer, more preferably greater than 90%, 95%,or 98%.

Groups A and B are the same or different and are independently selectedfrom H, halogen, C₁-C₄ alkyl, optionally substituted alkoxy includingaminoalkoxy, haloalkoxy and heteroarylalkoxy, alkoxyalkyl, haloalkyl,amino, nitro, alkylthio, acylamino, carbamoyl, or the following:

Synthesis

Compounds of formula (1), wherein Ar is pyridylene and X comprises—N(R⁹)— preferably may be prepared according to the proceduresillustrated in Scheme A. Dibromopyridine XIII or XIV is treated withamine RNH₂ to produce aminobromopyridine XV or XVI, respectively.Treatment of XV or XVI with diacetoxypalladium,diphenylphosphinoferrocene, DMF, diisopropylethylamine, andphenylenediamine under carbon monoxide yields anilinyl amide XVII orXVIII, respectively.

Treatment of XV or XVI with tert-butylacrylate, diisopropylethylamine,dibenzylacetone palladium, and tri-o-tolylphosphine (POT) in DMF undernitrogen affords compounds XIX and XX, respectively. The ester moiety ofXIX or XX is hydrolyzed to produce the corresponding acid moiety in XXIor XXII, respectively, by reaction with trifluoroacetic acid indichloromethane. Treatment of the acid XXI or XXII withphenylenediamine, BOP, and triethylamine affords the anilinyl amideXXIII or XXIV, respectively.

Compounds wherein X comprises —O—C(O)—NH— preferably may be preparedaccording to the synthetic route depicted in Scheme B. Thus, carbinolXXV is added to bromobenzylamine XXVI with carbonyldiimidazole (CDI),triethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF toproduce compound XXVII. The remaining synthetic steps in the productionof anilinyl amide XXVIII are as described above for Scheme A.

Compounds wherein X comprises —N(R⁹)—, preferably may be prepared asoutlined in Scheme C. Amine XXIX is reacted with p-bromobenzylbromide inthe presence of potassium carbonate in DMF to produce bromobenzylamineXXX. Treatment of XXX with nitroacrylanilide, dibenzylacetone palladium,POT, and diisopropylethylamine in DMF affords nitroanilide XXXI.Nitroanilide XXXI is converted to the corresponding anilinyl amide XXXIIby treatment with stannous chloride in methanol and water.

Treatment of amine XXXI in formic acid with paraformaldehyde providesmethylamine XXXIII. The nitroanilide moiety in XXXIII is then convertedto the corresponding anilinyl amide moiety in XXXIV by treatment withstannous chloride in methanol and water.

Alternatively, compounds wherein X comprises —N(R⁹)— may be preparedaccording to the synthetic route depicted in Scheme D. Carboxylic acidXXXV in methanol is treated with hydrochloric acid to produce esterXXXVI. Conversion of the primary amine moiety in XXXVI to the secondaryamine moiety in XXXVI is effected by treatment with a catalyst such astriethylamine, methoxybenzylchloride, sodium iodide, and potassiumcarbonate in DMF at 60° C. Ester XXXVI is converted to anilinyl amideXXXVII by treatment with sodium hydroxide, THF, and methanol, followedby BOP, triethylamine, and phenylenediamine in DMF, as described abovefor Scheme A.

Compounds wherein X comprises

or —C(O)—NH—, preferably may be prepared according to the proceduresillustrated in Scheme E. Addition of amine 68 to haloaryl compoundXXXVIII or XXXIX and potassium carbonate in DMF provides arylamine XL orXLI, respectively. Anilinyl amide XLII or XLIII is then prepared usingprocedures analogous to those set forth in Schemes A-D above.

Compounds such as XLVII and XLIX preferably may be prepared as outlinedin Scheme F. Dibromopyridine is combined with diaminoethane to produceamine XLIV. Treatment of amine XLIV with isatoic anhydride LV inmethanol and water, followed by refluxing in formic acid affordscompound XLVI. Treatment of amine XLIV with the reaction products ofbenzylaminodiacetic acid and acetic anhydride provides compound XLVIII.Bromopyridylamines XLVI and XLVIII are then converted to thecorresponding diene anilinylamides XLVII and XLIX, respectively, byprocedures analogous to those set forth in Schemes A-E above.

Compounds such as LIV preferably may be prepared according to thesynthetic route depicted in Scheme G. Trichlorotriazine is treated withaminoindan and diisopropylethylamine to produce dichloroaminotriazine L.Treatment with bromobenzylamine and diisopropylethylamine affordsdiaminochlorotriazine LI. Addition of ammonia gas and dioxane providestriaminotriazine LII. Treatment with protected acrylanilide,triethylamine, POT, and dibenzylacetone palladium then yields dieneanilinylamide LIII, which is deprotected with trifluoroacetic acid toprovide the final product LIV.

Compounds of formula (1), wherein Ar is quinolylene and X comprises—N(R⁹)— preferably may be prepared according to the proceduresillustrated in Scheme H. Dihydroxyquinoline LV withdimethylaminopyridine (DMAP) in pyridine is treated withtrifluoromethanesulfonic anhydride to providebis(trifluoromethanesulfonyloxy)-quinoline LVI. Treatment of LVI withp-methoxybenzylamine affords aminoquinoline LVII. Anilinyl amides LVIIIand LIX are then prepared using procedures analogous to those describedabove.

Compounds wherein X comprises a sulfur atom preferably may be preparedas outlined in Scheme I. Bromide LX is converted to diaryl ester LXIusing procedures analogous to those described for Scheme D above. EsterLXI is converted to the corresponding acid LXIV by treatment with ahydroxide base, such as lithium hydroxide. Alternatively, ester LXI maybe treated with chloroethylmorphonline, sodium iodide, potassiumcarbonate, triethylamine, and tetrabutylammonium iodide (TBAI) in DMF toproduce ester LXIII, which is then converted to acid LXIV. Conversion ofthe acid LXIV to the anilinyl amide LXV is effected by treatment of theacid with 1,2-phenylenediamine in the presence of BOP reagent,triethylamine, and dimethylformamide (DMF).

Alternatively, compounds wherein X comprises a sulfur atom, may beprepared according to the procedures illustrated in Scheme J. Sulfanylanilinylamide LXVIII is prepared using procedures analogous to those setforth above.

Compounds wherein X comprises —N(R⁹)— preferably may be preparedaccording to the synthetic route depicted in Scheme K. Amino anilinylamide LXXI is prepared according to synthetic steps similar to thosedescribed above.

Compounds wherein X comprises a sulfur atom may be prepared as outlinedin Scheme L. Phenylenediamine is reacted with di-tert-butyldicarbonate,followed by iodobenzoic acid, dimethylaminopropylethylcarbodiimide,hydroxybenzotriazole, and triethylamine to provide protected anilinylamide LXXII. The iodide moiety of LXXII is converted to the methyl estermoiety of LXXIII using procedures analogous to those set forth above.The methyl ester moiety of LXXIII is converted to the hydroxyl moiety ofLXXIV by treatment with a reducing agent such as diisobutylaluminumhydride (DIBAL-H). Addition of the heterocyclylsulfhydryl compoundHet-SH with triphenylphosphine and diethylazodicarboxylate converts thehydroxyl moiety of LXXIV to the sulfanyl moiety of LXXV. LXXV isdeprotected with trifluoroacetic acid to afford the sulfanyl anilinylamide LXXVI.

Compounds wherein X is a chemical bond may be prepared according to thesynthetic route depicted in Scheme M. Thus, chloroarylanilinylamideLXXVII is treated with aryl boronic acid, benzene, ethanol, aqueoussodium carbonate, and triphenylphosphine palladium to afford thediarylanilinylamide LXXVIII.

Compounds such as LXXXI preferably may be prepared according to theprocedures illustrated in Scheme N. Thus, benzene-1,2-carbaldehyde LXXIXin acetic acid is treated with p-aminomethylbenzoic acid to produce thebenzoic acid LXXX. The acid LXXX is converted to the correspondinganilinylamide LXXXI by treatment with hydroxybenzotriazole,ethylenedichloride, and phenylenediamine.

Compounds such as LXXXVI and LXXXIX preferably may be prepared accordingto the procedures illustrated in Scheme O. Phthalic anhydride LXXXV andp-aminomethylbenzoic acid are combined in acetic acid to produce anintermediate carboxylic acid, which is converted to the anilinylamideLXXXVI using procedures analogous to those set forth above.

The addition of 4-(2-aminoethyl)phenol to phthalic anhydride LXXXV inacetic acid affords the hydroxyl compound LXXXVII. The hydroxyl group ofLXXXVII is converted to the triflate group of LXXXVIII by treatment withsodium hydride, THF, DMF, and phenylaminoditriflate. Treatment ofLXXXVIII according to procedures analogous to those described for Scheme3 above affords the anilinylamide LXXXIX.

Compounds such as XCI-XCVI preferably may be prepared according to thesynthetic route depicted in Scheme P. Treatment of isatoic anhydride XCwith p-aminomethylbenzoic acid in water and triethylamine, followed byformic acid affords an intermediate carboxylic acid, which is convertedto anilinylamide XCI using procedures analogous to those describedabove.

Alternatively, treatment of isatoic acid XC with p-aminomethylbenzoicacid in water and triethylamine, followed by hydrochloric acid andsodium nitrite affords an intermediate carboxylic acid, which isconverted to anilinylamide XCII using procedures analogous to thosedescribed above.

Alternatively, treatment of isatoic acid XC with p-aminomethylbenzoicacid in water and triethylamine affords benzoic acid XCIII. Treatment ofXCIII with sodium hydroxide, dioxane, methylchloroformate, and methanolaffords an intermediate quinazolinedione carboxylic acid, the acidmoiety of which is then converted to the anilinylamide moiety of XCIVusing procedures analogous to those described above. Alternatively, theintermediate quanzolinedione carboxylic acid in DMF is treated withpotassium carbonate and methyl iodide to produce an intermediate benzoicacid methyl ester, which is converted to an intermediate benzoic acid bytreatment with sodium hydroxide, methanol, and water. The benzoic acidis then converted to the corresponding anilinylamide XCV usingprocedures analogous to those described above.

Alternatively, treatment of XCIII with acetic anhydride followed byacetic acid produces an intermediate carboxylic acid, which is convertedto anilinylamide XCVI using procedures analogous to those describedabove.

Compounds such as C preferably may be prepared as outlined in Scheme Q.Alkylamine XCVII is treated with thiocarbonyl diimidazole indichloromethane, followed by ammonium hydroxide to afford thioureaXCVIII. Treatment of thiourea XCVIII with methylmethoxyacrylate indioxane and N-bromosuccinimide produces thiazole ester IC. The ester ICis converted to the corresponding anilinylamine C using proceduresanalogous to those set forth above.

Compounds wherein X is a chemical bond and Cy has an amino substituentmay be prepared according to the synthetic route depicted in R. Thus,protected iodoarylanilinylamide CI is treated according to proceduresanalogous to those described above to afford the diarylanilinylamideCII. The aldehyde moiety in CII is converted to the correspondingsecondary amine moiety by treatment with the primary amine and sodiumtriacetoxyborohydride followed by glacial acetic acid. The resultantcompound is deprotected to yield CIII using procedures analogous tothose set forth in above.

Compounds wherein X comprises an alkynylene moiety may be prepared asoutlined in Scheme S. Treatment of protected iodoarylanilinylamide CIwith triphenylphosphine palladium chloride, cuprous iodide, and1-ethynylcyclohexylamine affords the alkynylarylanilinylamide CIV. Theprimary amine moiety in CIV is converted to the corresponding secondaryamine and the aniline moiety is deprotected to afford CV usingprocedures analogous to those described above.

Compounds such as CVIII preferably may be prepared according to thesynthetic route depicted in Scheme T. Dichloroaminotriazine CVI istreated with methyl-4-aminobenzoate in the presence ofdiisopropylethylamine to produce diaminotriazine CVII. Addition ofammonia gas and dioxane, followed by a saponification and a peptidecoupling to yield CVIII.

Compounds such as CX preferably may be prepared according to thesynthetic route depicted in Scheme U. The Grignard reaction oftrichloroaminotriazine with various alkyl magnesium bromide, followed bya treatment with methyl-4-aminobenzoate in the presence ofdiisopropylethylamine yields alkylaminotriazine CIX. Synthetic methodssimilar to those set forth above are then used to convert ester CIX tothe corresponding anilinyl amide CX.

As shown in Scheme V, amination of dichlorotriazine affords CXI. Stillcoupling using vinyl stannane provides CXII. Treatment with protectediodoanilide, triethylamine, POT and dibenzylacetone palladium thenyields anilinylamide, which is deprotected with trifluoroacetic acid toprovide the alkene CXIII. Hydrogenation of the alkene affords the finalcompound CXIV.

Compounds such as CXVIII preferably may be prepared according to thesynthetic route depicted in Scheme W. Treatment ofmethoxyaminobenzothiazole with tribromide boron affords thecorresponding acid CXV. Mitsunobu reaction using hydroxyethyl morpholinein the presence of diethylazodicarboxylate and triphenylphosphine yieldsthe amine CXVI. Reductive amination with methyl-4-formylbenzoate usingphenylsilane and tin catalyst yields to the ester CXVII. Saponificationfollowed by the usual peptide coupling analogous to those describedabove provides the desired anilide CXVIII.

Treatment 4-methylcyanobenzoic acid with hydrogen sulfide affords CXIX,which is subjected to cyclization in the presence of 1,3-dichloroacetoneto yield CXX. Treatment with morpholine followed by a peptide couplingusing the standard condition produces CXXI.

Compounds such as CXXIII and CXXVII preferably may be prepared accordingto the synthetic scheme Y. Consecutive treatment of acetyl acetone withmethyl bromomethylbenzoate in the presence of NaOMe and phenyl hydrazinefollowed by saponification, afforded the intermediate acid CXXII. Thismaterial was coupled with 1,2-diaminobenzene in a standard fashion toafford CXXIII.

Consecutive treatment of acetyl acetone with methyl bromomethylbenzoatein the presence of NaOMe and a 1:1 mixture AcOH—HCl (conc.) afforded theintermediate acid CXXIV. This keto-acid reacting with sulfur andmalonodinitrile in the presence of a base, produced the thiophene CXXV,which was converted into the desired CXXVII using standard procedures.

Compounds such as CXXX preferably may be prepared according to thesynthetic scheme Z. Treatment of 4-cyanomethylbenzoic acid withhydroxylamine produced the amidoxime CXXVIII, which upon treatment withacetic anhydride was converted into the oxadiazole CXXIX. The latter wascoupled with 1,2-diaminobenzene in a standard fashion to afford CXXX.

Compounds such as CXXXIII preferably may be prepared according to thesynthetic route depicted in Scheme AA. Treatment of 4-formylbenzoic acidwith thionyl chloride afford the acyl chloride which is coupled withprotected anilide to produce CXXXI. Reductive amination withdimethoxyaniline using phenylsilane and tin catalyst yields to theprotected anilide CXXXII. Treatment with isocyanate followed bydeprotection with trifluoroacetic acid provides the ureidoanilideCXXXIII.

Pharmaceutical Compositions

In a second aspect, the invention provides pharmaceutical compositionscomprising an inhibitor of histone deacetylase according to theinvention and a pharmaceutically acceptable carrier, excipient, ordiluent. Compounds of the invention may be formulated by any method wellknown in the art and may be prepared for administration by any route,including, without limitation, parenteral, oral, sublingual,transdermal, topical, intranasal, intratracheal, or intrarectal. Incertain preferred embodiments, compounds of the invention areadministered intravenously in a hospital setting. In certain otherpreferred embodiments, administration may preferably be by the oralroute.

The characteristics of the carrier will depend on the route ofadministration. As used herein, the term “pharmaceutically acceptable”means a non-toxic material that is compatible with a biological systemsuch as a cell, cell culture, tissue, or organism, and that does notinterfere with the effectiveness of the biological activity of theactive ingredient(s). Thus, compositions according to the invention maycontain, in addition to the inhibitor, diluents, fillers, salts,buffers, stabilizers, solubilizers, and other materials well known inthe art. The preparation of pharmaceutically acceptable formulations isdescribed in, e.g., Remington's Pharmaceutical Sciences, 18th Edition,ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

As used herein, the term pharmaceutically acceptable salts refers tosalts that retain the desired biological activity of theabove-identified compounds and exhibit minimal or no undesiredtoxicological effects. Examples of such salts include, but are notlimited to acid addition salts formed with inorganic acids (for example,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid,polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid,and polygalacturonic acid. The compounds can also be administered aspharmaceutically acceptable quaternary salts known by those skilled inthe art, which specifically include the quaternary ammonium salt of theformula —NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is acounterion, including chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,benzyloate, and diphenylacetate).

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutically effective amount without causing serious toxic effectsin the patient treated. A preferred dose of the active compound for allof the above-mentioned conditions is in the range from about 0.01 to 300mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about25 mg per kilogram body weight of the recipient per day. A typicaltopical dosage will range from 0.01-3% wt/wt in a suitable carrier. Theeffective dosage range of the pharmaceutically acceptable derivativescan be calculated based on the weight of the parent compound to bedelivered. If the derivative exhibits activity in itself, the effectivedosage can be estimated as above using the weight of the derivative, orby other means known to those skilled in the art.

Inhibition of Histone Deacetylase

In a third aspect, the invention provides a method of inhibiting histonedeacetylase in a cell, comprising contacting a cell in which inhibitionof histone deacetylase is desired with an inhibitor of histonedeacetylase according to the invention. Because compounds of theinvention inhibit histone deacetylase, they are useful research toolsfor in vitro study of the role of histone deacetylase in biologicalprocesses. In addition, the compounds of the invention selectivelyinhibit certain isoforms of HDAC.

Measurement of the enzymatic activity of a histone deacetylase can beachieved using known methodologies. For example, Yoshida et al., J.Biol. Chem., 265: 17174-17179 (1990), describes the assessment ofhistone deacetylase enzymatic activity by the detection of acetylatedhistones in trichostatin A treated cells. Taunton et al., Science, 272:408-411 (1996), similarly describes methods to measure histonedeacetylase enzymatic activity using endogenous and recombinant HDAC-1.

In some preferred embodiments, the histone deacetylase inhibitorinteracts with and reduces the activity of all histone deacetylases inthe cell. In some other preferred embodiments according to this aspectof the invention, the histone deacetylase inhibitor interacts with andreduces the activity of fewer than all histone deacetylases in the cell.In certain preferred embodiments, the inhibitor interacts with andreduces the activity of one histone deacetylase (e.g., HDAC-1) or asub-group of histone deacetylases (e.g., HDAC-1, HDAC-2, and HDAC-3) toa greater extent than other histone deacetylases. Where the inhibitorpreferentially reduces the activity of a sub-group of histonedeacetylases, the reduction in activity of each member of the sub-groupmay be the same or different. As discussed below, certain particularlypreferred histone deacetylase inhibitors are those that interact with,and reduce the enzymatic activity of, histone deacetylases that areinvolved in tumorigenesis. Certain other preferred histone deacetylaseinhibitors interact with and reduce the enzymatic activity of fungalhistone deacetylases.

Preferably, the method according to the third aspect of the inventioncauses an inhibition of cell proliferation of the contacted cells. Thephrase “inhibiting cell proliferation” is used to denote an ability ofan inhibitor of histone deacetylase to retard the growth of cellscontacted with the inhibitor as compared to cells not contacted. Anassessment of cell proliferation can be made by counting contacted andnon-contacted cells using a Coulter Cell Counter (Coulter, Miami, Fla.)or a hemacytometer. Where the cells are in a solid growth (e.g., a solidtumor or organ), such an assessment of cell proliferation can be made bymeasuring the growth with calipers and comparing the size of the growthof contacted cells with non-contacted cells.

Preferably, growth of cells contacted with the inhibitor is retarded byat least 50% as compared to growth of non-contacted cells. Morepreferably, cell proliferation is inhibited by 100% (i.e., the contactedcells do not increase in number). Most preferably, the phrase“inhibiting cell proliferation” includes a reduction in the number orsize of contacted cells, as compared to non-contacted cells. Thus, aninhibitor of histone deacetylase according to the invention thatinhibits cell proliferation in a contacted cell may induce the contactedcell to undergo growth retardation, to undergo growth arrest, to undergoprogrammed cell death (i.e., to apoptose), or to undergo necrotic celldeath.

The cell proliferation inhibiting ability of the histone deacetylaseinhibitors according to the invention allows the synchronization of apopulation of asynchronously growing cells. For example, the histonedeacetylase inhibitors of the invention may be used to arrest apopulation of non-neoplastic cells grown in vitro in the G1 or G2 phaseof the cell cycle. Such synchronization allows, for example, theidentification of gene and/or gene products expressed during the G1 orG2 phase of the cell cycle. Such synchronization of cultured cells mayalso be useful for testing the efficacy of a new transfection protocol,where transfection efficiency varies and is dependent upon theparticular cell cycle phase of the cell to be transfected. Use of thehistone deacetylase inhibitors of the invention allows thesynchronization of a population of cells, thereby aiding detection ofenhanced transfection efficiency.

In some preferred embodiments, the contacted cell is a neoplastic cell.The term “neoplastic cell” is used to denote a cell that shows aberrantcell growth. Preferably, the aberrant cell growth of a neoplastic cellis increased cell growth. A neoplastic cell may be a hyperplastic cell,a cell that shows a lack of contact inhibition of growth in vitro, abenign tumor cell that is incapable of metastasis in vivo, or a cancercell that is capable of metastasis in vivo and that may recur afterattempted removal. The term “tumorigenesis” is used to denote theinduction of cell proliferation that leads to the development of aneoplastic growth. In some embodiments, the histone deacetylaseinhibitor induces cell differentiation in the contacted cell. Thus, aneoplastic cell, when contacted with an inhibitor of histone deacetylasemay be induced to differentiate, resulting in the production of anon-neoplastic daughter cell that is phylogenetically more advanced thanthe contacted cell.

In some preferred embodiments, the contacted cell is in an animal. Thus,the invention provides a method for treating a cell proliferativedisease or condition in an animal, comprising administering to an animalin need of such treatment a therapeutically effective amount of ahistone deacetylase inhibitor of the invention. Preferably, the animalis a mammal, more preferably a domesticated mammal. Most preferably, theanimal is a human.

The term “cell proliferative disease or condition” is meant to refer toany condition characterized by aberrant cell growth, preferablyabnormally increased cellular proliferation. Examples of such cellproliferative diseases or conditions include, but are not limited to,cancer, restenosis, and psoriasis. In particularly preferredembodiments, the invention provides a method for inhibiting neoplasticcell proliferation in an animal comprising administering to an animalhaving at least one neoplastic cell present in its body atherapeutically effective amount of a histone deacetylase inhibitor ofthe invention.

It is contemplated that some compounds of the invention have inhibitoryactivity against a histone deacetylase from a protozoal source. Thus,the invention also provides a method for treating or preventing aprotozoal disease or infection, comprising administering to an animal inneed of such treatment a therapeutically effective amount of a histonedeacetylase inhibitor of the invention. Preferably the animal is amammal, more preferably a human. Preferably, the histone deacetylaseinhibitor used according to this embodiment of the invention inhibits aprotozoal histone deacetylase to a greater extent than it inhibitsmammalian histone deacetylases, particularly human histone deacetylases.

The present invention further provides a method for treating a fungaldisease or infection comprising administering to an animal in need ofsuch treatment a therapeutically effective amount of a histonedeacetylase inhibitor of the invention. Preferably the animal is amammal, more preferably a human. Preferably, the histone deacetylaseinhibitor used according to this embodiment of the invention inhibits afungal histone deacetylase to a greater extent than it inhibitsmammalian histone deacetylases, particularly human histone deacetylases.

The term “therapeutically effective amount” is meant to denote a dosagesufficient to cause inhibition of histone deacetylase activity in thecells of the subject, or a dosage sufficient to inhibit cellproliferation or to induce cell differentiation in the subject.Administration may be by any route, including, without limitation,parenteral, oral, sublingual, transdermal, topical, intranasal,intratracheal, or intrarectal. In certain particularly preferredembodiments, compounds of the invention are administered intravenouslyin a hospital setting. In certain other preferred embodiments,administration may preferably be by the oral route.

When administered systemically, the histone deacetylase inhibitor ispreferably administered at a sufficient dosage to attain a blood levelof the inhibitor from about 0.01 μM to about 100 μM, more preferablyfrom about 0.05 μM to about 50 μM, still more preferably from about 0.1μM to about 25 μM, and still yet more preferably from about 0.5 μM toabout 25 μM. For localized administration, much lower concentrationsthan this may be effective, and much higher concentrations may betolerated. One of skill in the art will appreciate that the dosage ofhistone deacetylase inhibitor necessary to produce a therapeutic effectmay vary considerably depending on the tissue, organ, or the particularanimal or patient to be treated.

In certain preferred embodiments of the third aspect of the invention,the method further comprises contacting the cell with an antisenseoligonucleotide that inhibits the expression of a histone deacetylase.The combined use of a nucleic acid level inhibitor (e.g., antisenseoligonucleotide) and a protein level inhibitor (i.e., inhibitor ofhistone deacetylase enzyme activity) results in an improved inhibitoryeffect, thereby reducing the amounts of the inhibitors required toobtain a given inhibitory effect as compared to the amounts necessarywhen either is used individually. The antisense oligonucleotidesaccording to this aspect of the invention are complementary to regionsof RNA or double-stranded DNA that encode HDAC-1, HDAC-2, HDAC-3,HDAC-4, HDAC-5, HDAC-6, HDAC7, and/or HDAC-8 (see e.g., GenBankAccession Number U50079 for HDAC-1, GenBank Accession Number U31814 forHDAC-2, and GenBank Accession Number U75697 for HDAC-3).

For purposes of the invention, the term “oligonucleotide” includespolymers of two or more deoxyribonucleosides, ribonucleosides, or2′-substituted ribonucleoside residues, or any combination thereof.Preferably, such oligonucleotides have from about 6 to about 100nucleoside residues, more preferably from about 8 to about 50 nucleosideresidues, and most preferably from about 12 to about 30 nucleosideresidues. The nucleoside residues may be coupled to each other by any ofthe numerous known internucleoside linkages. Such internucleosidelinkages include without limitation phosphorothioate,phosphorodithioate, alkylphosphonate, alkylphosphonothioate,phosphotriester, phosphoramidate, siloxane, carbonate,carboxymethylester, acetamidate, carbamate, thioether, bridgedphosphoramidate, bridged methylene phosphonate, bridged phosphorothioateand sulfone internucleoside linkages. In certain preferred embodiments,these internucleoside linkages may be phosphodiester, phosphotriester,phosphorothioate, or phosphoramidate linkages, or combinations thereof.The term oligonucleotide also encompasses such polymers havingchemically modified bases or sugars and/or having additionalsubstituents, including without limitation lipophilic groups,intercalating agents, diamines and adamantane.

For purposes of the invention the term “2′-substituted ribonucleoside”includes ribonucleosides in which the hydroxyl group at the 2′ positionof the pentose moiety is substituted to produce a 2′-O-substitutedribonucleoside. Preferably, such substitution is with a lower alkylgroup containing 1-6 saturated or unsaturated carbon atoms, or with anaryl or allyl group having 2-6 carbon atoms, wherein such alkyl, aryl orallyl group may be unsubstituted or may be substituted, e.g., with halo,hydroxy, trifluoromethyl, cyano, nitro, acyl, acyloxy, alkoxy, carboxyl,carbalkoxyl, or amino groups. The term “2′-substituted ribonucleoside”also includes ribonucleosides in which the 2′-hydroxyl group is replacedwith an amino group or with a halo group, preferably fluoro.

Particularly preferred antisense oligonucleotides utilized in thisaspect of the invention include chimeric oligonucleotides and hybridoligonucleotides.

For purposes of the invention, a “chimeric oligonucleotide” refers to anoligonucleotide having more than one type of internucleoside linkage.One preferred example of such a chimeric oligonucleotide is a chimericoligonucleotide comprising a phosphorothioate, phosphodiester orphosphorodithioate region, preferably comprising from about 2 to about12 nucleotides, and an alkylphosphonate or alkylphosphonothioate region(see e.g., Pederson et al. U.S. Pat. Nos. 5,635,377 and 5,366,878).Preferably, such chimeric oligonucleotides contain at least threeconsecutive internucleoside linkages selected from phosphodiester andphosphorothioate linkages, or combinations thereof.

For purposes of the invention, a “hybrid oligonucleotide” refers to anoligonucleotide having more than one type of nucleoside. One preferredexample of such a hybrid oligonucleotide comprises a ribonucleotide or2′-substituted ribonucleotide region, preferably comprising from about 2to about 12 2′-substituted nucleotides, and a deoxyribonucleotideregion. Preferably, such a hybrid oligonucleotide contains at leastthree consecutive deoxyribonucleosides and also containsribonucleosides, 2′-substituted ribonucleosides, preferably2′-O-substituted ribonucleosides, or combinations thereof (see e.g.,Metelev and Agrawal, U.S. Pat. No. 5,652,355).

The exact nucleotide sequence and chemical structure of an antisenseoligonucleotide utilized in the invention can be varied, so long as theoligonucleotide retains its ability to inhibit expression of the gene ofinterest. This is readily determined by testing whether the particularantisense oligonucleotide is active. Useful assays for this purposeinclude quantitating the mRNA encoding a product of the gene, a Westernblotting analysis assay for the product of the gene, an activity assayfor an enzymatically active gene product, or a soft agar growth assay,or a reporter gene construct assay, or an in vivo tumor growth assay,all of which are described in detail in this specification or inRamchandani et al. (1997) Proc. Natl. Acad. Sci. USA 94: 684-689.

Antisense oligonucleotides utilized in the invention may conveniently besynthesized on a suitable solid support using well known chemicalapproaches, including H-phosphonate chemistry, phosphoramiditechemistry, or a combination of H-phosphonate chemistry andphosphoramidite chemistry (i.e., H-phosphonate chemistry for some cyclesand phosphoramidite chemistry for other cycles). Suitable solid supportsinclude any of the standard solid supports used for solid phaseoligonucleotide synthesis, such as controlled-pore glass (CPG) (see,e.g., Pon, R. T. (1993) Methods in Molec. Biol. 20: 465-496).

Particularly preferred oligonucleotides have nucleotide sequences offrom about 13 to about 35 nucleotides which include the nucleotidesequences shown in Table 1. Yet additional particularly preferredoligonucleotides have nucleotide sequences of from about 15 to about 26nucleotides of the nucleotide sequences shown in Table 1. TABLE 1position Accession Nucleotide within Oligo Target Number PositionSequence Gene HDAC1 AS1 Human HDAC1 U50079 1585-16045′-GAAACGTGAGGGACTCAGCA-3′ 3′-UTR HDAC1 AS2 Human HDAC1 U50079 1565-15845′-GGAAGCCAGAGCTGGAGAGG-3′ 3′-UTR HDAC1 MM Human HDAC1 U50079 1585-16045′-GTTAGGTGAGGCACTGAGGA-3′ 3′-UTR HDAC2 AS Human HDAC2 U31814 1643-16225′-GCTGAGCTGTTCTGATTTGG-3′ 3′-UTR HDAC2 MM Human HDAC2 U31814 1643-16225′-CGTGAGCACTTCTCATTTCC-3′ 3′-UTR HDAC3 AS Human HDAC3 AF0397031276-1295 5′-CGCTTTCCTTGTCATTGACA-3′ 3′-UTR HDAC3 MM Human HDAC3AF039703 1276-1295 5′-GCCTTTCCTACTCATTGTGT-3′ 3′-UTR HDAC4 AS1 HumanHDAC4 AB006626  514-33 5′-GCTGCCTGCCGTGCCCACCC-3′ 5′-UTR HDAC4 MM1 HumanHDAC4 AB006626  514-33 5′-CGTGCCTGCGCTGCCCACGG-3′ 5′-UTR HDAC4 AS2 HumanHDAC4 AB006626 7710-29 5′-TACAGTCCATGCAACCTCCA-3′ 3′-UTR HDAC4 MM4 HumanHDAC4 AB006626 7710-29 5′-ATCAGTCCAACCAACCTCGT-3′ 3′-UTR HDAC5 AS HumanHDAC5 AF039691 2663-2682 5′-CTTCGGTCTCACCTGCTTGG-3′ 3′-UTR HDAC6 ASHuman HDAC6 AJ011972 3791-3810 5′-CAGGCTGGAATGAGCTACAG-3′ 3′-UTR HDAC6MM Human HDAC6 AJ011972 3791-3810 5′-GACGCTGCAATCAGGTAGAC-3′ 3′-UTRHDAC7 AS Human HDAC7 AF239243 2896-2915 5′-CTTCAGCCAGGATGCCCACA-3′3′-UTR HDAC8 AS1 Human HDAC8 AF230097   51-70 5′-CTCCGGCTCCTCCATCTTCC-3′5′-UTR HDAC8 AS2 Human HDAC8 AF230097 1328-13475′-AGCCAGCTGCCACTTGATGC-3′ 3′-UTR

The following examples are intended to further illustrate certainpreferred embodiments of the invention, and are not intended to limitthe scope of the invention.

EXAMPLES

Example 1N-(2-Amino-phenyl)-3-[4-({(2-hydroxy-ethyl)-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-acrylamide(6) Step 1: Methyl 3-(4-formyl-phenyl)-acrylate (1)

To a stirred suspension at room temperature of 4-formylcinnamic acid(15.39 g, 87.36 mmol) in 1,2-dichloroethane (100 mL) was addedconcentrated sulfuric acid (8 mL) and anhydrous MeOH (15 mL),respectively. The reaction mixture was refluxed for 18 h, cooled to theroom temperature and concentrated. The residue was diluted with AcOEtand washed with H₂O, saturated aqueous NaHCO₃, H₂O and brine, dried overMgSO₄, filtered, and concentrated again. The crude product was purifiedby flash chromatography on silica gel (eluent AcOEt/hexane:20/80→30/70)to afford the title compound 2 (9.75 g, 51.26 mmol, 59% yield) as a paleyellow powder. ¹H NMR (300 MHz, CDCl₃) δ(ppm): 10.04 (s, 1H), 7.91 (d,J=7.9 Hz, 2H), 7.80-7.60 (m, 3H), 6.56 (d, J=15.8 Hz, 1H), 3.84 (s, 3H).

Step 2: Methyl3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-acrylate (2)

To a stirred solution of 1 (3.00 g, 15.77 mmol) and tryptamine (2.78 g,17.35 mmol) in anhydrous 1,2-dichloroethane (200 mL) under nitrogen wasadded NaBH(OAc)₃ (3.87 g, 17.35 mmol) at room temperature. The reactionmixture was stirred at room temperature for 39 hours, poured into 10%solution of K₂CO₃ and extracted with CH₂Cl₂. The organic layer wasconcentrated to form a residue which was purified by flashchromatography on silica gel (MeOH/CH₂Cl₂, 10/90) and co-precipitated ina mixture of AcOEt/hexane to afford the title compound 2 (4.39 g, 13.13mmol, 83% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm):10.78 (s, 1H), 7.70-7.62 (m, 3H), 7.49 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.2Hz, 2H), 7.33 (dt, J=8.0, 0.9 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.06(ddd, J=7.0, 7.0, 1.2 Hz, 1H), 6.96 (ddd, J=6.9, 6.9, 1.1 Hz, 1H), 6.62(d, J=16.0 Hz, 1H), 3.79 (s, 2H), 3.75 (s, 3H), 2.91-2.78 (m, 4H), 2.18(bs, 1H).

Step 3: Methyl3-[4-({[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-acrylate(3)

To a stirred solution of 2 (2.82 g, 8.44 mmol) and diisopropylethylamine(2.21 mL, 12.66 mmol) in anhydrous DMSO (22 mL) at room temperatureunder nitrogen was added (2-bromo-ethoxy)-tert-butyl-dimethylsilane(2.17 mL, 10.12 mmol). The reaction mixture was heated at 50-55° C. for24 h, poured into water and extracted with CH₂Cl₂. The organic layer wasdried over MgSO₄, filtered, and concentrated. The crude product waspurified by flash chromatography on silica gel (AcOEt/CH₂Cl₂, 15/85,plus a few drops of NH₄OH) to afford the title compound 3 (4.06 g, 8.24mmol, 97% yield) as a dark orange oil. ¹H NMR (300 MHz, CDCl₃) δ(ppm):7.95 (bs, 1H), 7.70 (d, J=15.8 Hz, 1H), 7.58-7.30 (m, 6H), 7.18 (t,J=7.5 Hz, 1H), 7.07 (t, J=7.5 Hz, 1H), 7.00 (bs, 1H), 6.43 (d, J=16.2Hz, 1H), 3.88-3.68 (m, 7H), 3.04-2.66 (m, 6H), 0.88 (bs, 9H), 0.04 (bs,6H).

Step 4:3-[4-({[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-acrylicacid (4)

To a stirred solution of compound 3 (3.18 g, 6.45 mmol) in THF (40 mL)was added a solution of LiOH.H₂O (677 mg, 16.14 mmol) in water (20 mL)at room temperature. After 24 h the reaction mixture was concentrated,diluted with water and acidified with 1N HCl until a pH 5-6. Aprecipitate was formed which was separated by filtration, rinsed withwater and dried to afford the title compound 4 (2.43 g, 5.08 mmol, 79%yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.34(bs, 1H), 10.75 (s, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.59 (d, J=15.8 Hz,1H), 7.44-7.35 (m, 3H), 7.32 (d, J=8.0 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H),7.05 (td, J=7.5, 1.0 Hz, 1H), 6.92 (td, J=7.4, 0.9 Hz, 1H), 6.51 (d,J=15.8 Hz, 1H), 3.79 (s, 2H), 3.69 (t, J=6.4 Hz, 2H), 2.93-2.74 (m, 4H),2.69 (t, J=6.2 Hz, 2H), 0.88 (s, 9H), 0.05 (s, 6H).

Step 5:N-(2-Amino-phenyl)-3-[4-({[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-acrylamide(5)

To a stirred solution of 4 (1.30 g, 2.72 mmol) in anhydrous DMF (20 mL)at room temperature under nitrogen were added Et₃N (330 μl, 3.26 mmol)and BOP reagent (1.32 g, 2.99 mmol), respectively. After 30 min, asolution of 1,2-phenylenediamine (352 mg, 3.26 mmol), Et₃N (1.14 mL,8.15 mmol) in anhydrous DMF (3 mL) was added dropwise. After 3 h thereaction mixture was poured into saturated aqueous solution of NH₄Cl,and extracted with AcOEt. The extract was washed with saturated NH₄Cl,water and brine, dried over MgSO₄, filtered, concentrated and purifiedby flash chromatography on silica gel (MeOH/CH₂Cl₂, 5/95 plus severaldrops of NH₄OH), to afford the title compound 5 (1.49 g, 2.62 mmol, 96%yield) as a yellow sticky foam. ¹H NMR (300 MHz, DMSO-d₆) δ(ppm): 10.78(s, 1H), 9.40 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.58 (d, J=15.8 Hz, 1H),7.45 (d, J=7.9 Hz, 2H), 7.40 (t, J=7.7 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H),7.14 (s, 1H), 7.07 (t, J=7.5 Hz, 1H), 7.05-6.85 (m, 3H), 6.79 (d, J=7.9Hz, 1H), 6.62 (t, J=7.5 Hz, 1H), 4.98 (bs, 2H), 3.80 (s, 2H), 3.71 (t,J=6.2 Hz, 2H), 2.95-2.75 (m, 4H), 2.71 (t, J=6.2 Hz, 2H), 0.89 (s, 9H),0.05 (s, 6H).

Step 6:N-(2-Amino-phenyl)-3-[4-({(2-hydroxy-ethyl)-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-acrylamide(6)

To a stirred solution at −20° C. of 5 (1.49 g, 2.62 mmol) in anhydrousTHF (30 mL) under nitrogen was slowly added a solution of TBAF (2.88 mL,2.88 mmol, 1.0M in THF). The reaction mixture was allowed to warm-up tothe room temperature over 1 h and was stirred for additional 22 hours.MeOH was added and the reaction mixture was concentrated, diluted withAcOEt, and successively washed with saturated aqueous solution ofNaHCO₃, H₂O, a saturated aqueous solution of NH₄Cl and brine, dried overMgSO₄, filtered, and concentrated. The residue was purified by flashchromatography on silica gel (MeOH/CH₂Cl₂, 5/95→10/90 plus several dropsof NH₄OH) and triturated with a mixture of AcOEt/CH₂Cl₂/hexane to affordthe title compound 6 (956 mg, 2.10 mmol, 80% yield) as a pale yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 10.76 (s, 1H), 9.39 (s, 1H), ABsystem (δ_(A)=7.58, δ_(B)=7.44, J_(AB)=8.0 Hz, 4H), 7.56 (d, J=15.7 Hz,1H), 7.42-7.34 (m, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H),7.05 (td, J=7.2, 1.2 Hz, 1H), 6.98-6.90 (m, 2H), 6.90 (d, J=15.8 Hz,1H), 6.77 (dd, J=8.0, 1.4 Hz, 1H), 6.60 (ddd, J=7.5, 7.5, 1.4 Hz, 1H),4.98 (bs, 2H), 4.43 (t, J=5.4 Hz, 1H), 3.78 (s, 2H), 3.56 (td, J=6.3,5.6 Hz, 2H), 2.94-2.84 (m, 2H), 2.82-2.74 (m, 2H), 2.68 (t, J=6.5 Hz,2H).

Example 2N-(2-Amino-phenyl)-4-({4-[2-(3,4-dimethoxy-phenyl)-ethylamino]-pyrimidin-2-ylamino}-methyl)-benzamide(10a) Step 1:(2-Chloro-pyrimidin-4-yl)-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine (7)

To a stirred solution of 2,4-dichloropyrimidine (500 mg, 3.36 mmol) inanhydrous DMF (10 mL) at room temperature under nitrogen were slowlyadded i-Pr₂NEt (1.06 mL, 6.10 mmol) and 3,4-dimethoxyphenethylamine (531μl, 3.05 mmol), respectively. After 24 h the reaction mixture wasdiluted with AcOEt and successively washed with saturated aqueoussolution of NH₄Cl and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The residue was purified by flash chromatography on silicagel (MeOH/CH₂Cl₂: 2/98→5/95) to afford the title compound 7a (744 mg,2.53 mmol, 83% yield) as pale yellow oil.

Step 2: Methyl4-({4-[2-(3,4-dimethoxy-phenyl)-ethylamino]-pyrimidin-2-ylamino}-methyl)-benzoate(8)

In a sealed flask, a mixture of 7 (744 mg, 2.53 mmol), methyl4-(aminomethyl)benzoate (628 mg, 3.80 mmol) and i-Pr₂NEt (882 μl, 5.07mmol) in isopropanol (50 mL) was heated to 120-125° C. for 7 days(during this period of time an excess of methyl 4-(aminomethyl)benzoatewas added to the reaction mixture). The reaction mixture was allowed tocool to the room temperature, concentrated and purified by flashchromatography on silica gel (MeOH/CH₂Cl₂, 5/95→10/90 plus several dropsof NH₄OH) to afford the title compound 8 (671 mg, 1.59 mmol, 63% yield)as an orange sticky solid.

Step 3:4-({4-[2-(3,4-Dimethoxy-phenyl)-ethylamino]-pyrimidin-2-ylamino}-methyl)-benzoicacid (9)

To a stirred solution of compound 8 (670 mg, 1.59 mmol) in THF (15 mL)at room temperature was added a solution of LiOH.H₂O (166 mg, 3.97 mmol)in water (5 mL). After 24 h, the reaction mixture was concentrated,diluted with water and acidified with 2N HCl (pH at 5-6). A precipitateformed, which was separated by filtration, rinsed with water and driedto afford the title compound 9 (600 mg, 1.47 mmol, 93% yield) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): AB system(δ_(A)=7.87, δ_(B)=7.41, J=8.2 Hz, 4H), 7.68-7.58 (m, 1H), 7.12-6.56 (m,5H), 5.75 (d, J=5.5 Hz, 1H), 4.53 (d, J=6.3 Hz, 2H), 3.74 and 3.72 (2s,6H), 3.48-3.30 (m, 2H), 2.80-2.60 (m, 2H).

Step 4:N-(2-Amino-phenyl)-4-({4-[2-(3,4-dimethoxy-phenyl)-ethylamino]-pyrimidin-2-ylamino}-methyl)-benzamide(10a)

To a stirred solution of 9a (300 mg, 0.73 mmol) in anhydrous DMF (10 mL)at room temperature under nitrogen were added Et₃N (123 μl, 0.88 mmol)and BOP reagent (358 mg, 0.81 mmol), respectively. After 30 min, asolution of 1,2-phenylenediamine (95 mg, 0.88 mmol), Et₃N (307 μl, 2.20mmol) in anhydrous DMF (2 mL) was added drop wise. After stirringovernight, the reaction mixture was poured into a saturated aqueoussolution of NH₄Cl, and extracted with AcOEt. The organic layer wassuccessively washed with saturated NH₄Cl, water and brine, dried overMgSO₄, filtered, and concentrated. The residue was purified by flashchromatography on silica gel (MeOH/CH₂Cl₂: 5/95→10/90 plus a few dropsof NH₄OH) and co-precipitated in a mixture of AcOEt/MeOH/hexane toafford the title compound 10a (280 mg, 0.56 mmol, 76% yield) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.60 (s, 1H), ABsystem (δ_(A)=7.91, δ_(B)=7.43, J=8.0 Hz, 4H), 7.71-7.58 (m, 1H), 7.17(d, J=7.4 Hz, 1H), 7.20-7.00 (m, 2H), 6.98 (t, J=7.5 Hz, 1H), 6.86 (d,J=8.0 Hz, 1H), 6.84-6.64 (m, 3H), 6.61 (t, J=7.4 Hz, 1H), 5.76 (d, J=5.3Hz, 1H), 4.90 (bs, 2H), 4.54 (d, J=6.1 Hz, 2H), 3.74 (s, 6H), 3.50-3.35(m, 2H), 2.80-2.62 (m, 2H).

Examples 3-11

Examples 3-11 (compounds 10b-10j) were prepared using the sameprocedures as described for the compound 10a, example 2 (scheme 2).TABLE 1 10b-j

Cmpd Ex R-X Name Characterization 10b 3

N-(2-Amino-phenyl)- 4-({4-[2-(1H-indol-3- yl)-ethylamino]-pyrimidin-2-ylamino}- methyl)-benzamide ¹H NMR (400 MHz, DMSO-d₆)δ(ppm): 10.82 (s, 1H), 9.60 (s, 1H), AB system (δ_(Λ)= 7.90, δ_(B) =7.43, J_(AB) = 8.1 Hz, 4H), # 7.64 (bs, 1H), 7.52 (d, J = 7.2 Hz, 1H),7.34 (d, J = 8.0 Hz, 1H), 7.25-6.90 (m, 7H), 6.79 (dd, J = 8.0, 1.4 Hz,# 1H), 6.61 (td, J = 7.5, 1.4 Hz, 1H), 5.76 (d, J = 5.1 Hz, 1H), 4.90(s, 2H), 4.54 (d, J = 6.1 Hz, 2H), 3.63-3.43 (m, 2H), 2.93 (t, J = 7.3Hz, 2H). 10c 4

N-(2-Amino-phenyl)- 4-({4-[2-(3-methoxy- phenyl)-ethylamino]-pyrimidin-2-ylamino}- methyl)-benzamide ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.60 (s, 1H), AB system (δ_(Λ) = 7.91, δ_(B) =7.43, J = 8.2 Hz,4H), 7.64 (bs, 1H), 7.25- 6.92 (m, 5H), 6.87-6.68 (m, 4H), 6.61 (td, J =7.5, 1.4 Hz, 1H), 5.75 (d, J = 5.3 Hz, 1H), 4.90 (bs, 2H), 4.54 # (d, J= 6.3 Hz, 2H), 3.75 (s, 3H), 3.52-3.38 (m, 2H), 2.84- 2.70 (m, 2H). 10d5

N-(2-Amino-phenyl)- 4-{[4-(2-pyridin-3-yl- ethylamino)-pyrimidin-2-ylamino]- methyl}-benzamide ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.60 (s, 1H), 8.47-8.33 (m, 2H), AB system (δ_(Λ) = 7.91, δ_(B) =7.42, J = 8.0 Hz, 4H), 7.70-7.50 (m, 2H), 7.36-7.28 (m, 1H), 7.25-7.03(m, 2H), 7.17 (d, J = 7.4 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.79 # (d,J = 8.2 Hz, 1H), 6.61 (t, J = 7.5 Hz, 1H), 5.75 (d, J = 5.9 Hz, 1H),4.90 (bs, 2H), 4.53 (d, J = 6.1 Hz, 2H), 3.53-3.39 (m, 2H), 2.88-2.73(m, 2H). 10e 6

N-(2-Amino-phenyl)- 4-{[4-(2-morpholin-4- yl-ethylamino)-pyrimidin-2-ylamino]- methyl}-benzamide ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.61 (s, 1H), AB system (δ_(Λ) = 7.91, δ_(B) =7.41, J = 8.0 Hz,4H), 7.68-7.57 (m, 1H), 7.25-6.85 (m, 2H), 7.16 (d, J = 7.4 Hz, 1H),6.98 (t, J = 7.5 Hz, 1H), 6.79 (d, J =7.8 Hz, 1H), 6.61 (t, # J = 7.3Hz, 1H), 5.77 (d, J = 5.5 Hz, 1H), 4.90 (bs, 2H), 4.51 (d, J = 6.3 Hz,2H), 3.66-3.50 (m, 4H), 3.40- 3.26 (m, 2H), 2.50-2.24 (m, 6H). 10F 7

N-(2-Amino-phenyl)- 4-{[4-(4-methyl- piperazin-1-yl)-pyrimidin-2-ylamino]- methyl}-benzamide ¹H NMR (400 MHz, CD₃OD) δ (ppm):7.90 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 5.9 Hz, 1H), 7.44 (d, J = 8.2 Hz,2H), 7.16 (m, 1H), 7.06 (m, 1H), 6.89 (m, 1H), 6.75 (m, 1H), 6.05 (d, J= 6.7 Hz, 1H), 4.58 (s, 2H), 3.60 (m, 4H), 2.42 (m, 4H), 2.18 (s, 3H).10g 8

4-{[4-(4-Acetyl- piperazin-1-yl)- pyrimidin-2-ylamino]-methyl}-N-(2-amino- phenyl)-benzamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):9.78 (s, 1H), 8.71 (s, 1H), 7.96 (d, J = 7.8 Hz, 2H), 7.89 (d, J = 7.0Hz, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 7.8 Hz, 1H), 7.0 (dd, J= 7.8, 7.4 Hz, 1H), 6.86 (d, J =7.8 Hz, 1H), 6.70 (m, 1H), 6.51 (d, # J=7.0 Hz, 1H), 4.62 (d, J = 5.9 Hz, 2H), 3.76 (m, 4H), 3.34 (m, 6H), 2.03(s, 3H). 10h 9

N-(2-Amino-phenyl)- 4-{[4-(3,4,5- trimethoxy- phenylamino)-pyrimidin-2-ylamino]- methyl}-benzamide ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.50 (s, 1H), 9.07 (s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.74 (d, J= 5.7 Hz, 1H), 7.31(d, J = 8.0 Hz, 3H), 7.05 (d, J = 6.7 Hz, 1H), 6.96(s, 2H), 6.87 (m, 1H), 6.68 (m, 1H), 6.50 (m, 1H), 5.93 (d, J = 5.7 Hz,# 1H), 4.82 (bs, 2H), 4.54 (bs, 2H), 3.75-3.40 (m, 9H). 10i 10

N-(2-Amino-phenyl)- 4-{[4-(pyridin-3- yloxy)-pyrimidin-2-ylamino]-methyl}- benzamide ¹H NMR (500 MHz, DMSO-d₆) δ (ppm): 9.58 (s,1H), 8.49 (bs, 1H), 8.20 (m, 1H), 8.03 (bs, 1H), 7.81 (m, 3H), 7.59 (bs,1H), 7.50 (bs, 1H), 7.36 (bs, 1H), 7.14 (m, 1H), 7.04 (bs, 1H), 6.96 (m,1H), 6.76 (m, 1H), 6.59 (m, 1H), 6.28 (bs, 2H), 4.87 (s, 2H), 4.49 (s,1H), 4.16 (s, 1H). 10j 11

N-(2-Amino-phenyl)- 4-{[4-(3,4-dimethoxy- phenylsulfanyl)-pyrimidin-2-ylamino]- methyl}-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ(ppm): 9.64 (s, 1H), 8.03 (d, J = 5.3 Hz, 1H), 7.94 (m, 3H), 7.39 (bs,2H), 7.19 (m, 4H), 7.02 (dd, J = 7.5, 7.5 Hz, 1H), 6.84 (d, J = 7.5 Hz,1H), 6.66 (dd, J = 7.5, 7.5 Hz, 1H), 6.04 (bs, 1H), 4.93 (s, 2H), 4.53(bs, 2H), 3.88 # (s, 3H), 3.82 (s, 3H).

Example 12N-(2-Amino-phenyl)-4-([2,3′]bipyridinyl-6-ylaminomethyl)-benzamide (13a)Step 1: [2,3′]Bipyridinyl-6-ylamine (11)

To a stirred degassed suspension of a mixture of 2-amino-6-bromopyridine(5.38 g, 31.09 mmol), 2,4,6-(3-pyridinyl)-cyclotriboroxane (3.80 g,12.07 mmol) and aqueous Na₂CO₃ (100 mL, 0.4M) in acetonitrile (100 mL)at room temperature Pd(PPh₃)₄ (1.70 g, 1.47 mmol) was added. Thereaction mixture was heated at 95° for 1 to 2 days under nitrogen,cooled to the room temperature and filtered. The filtrate wasconcentrated purified by flash chromatography on silica gel(MeOH/CH₂Cl₂: 5/95→10/90 plus a few drops of NH₄OH) and co-precipitatedwith a mixture of AcOEt/CH₂Cl₂/hexane to afford the title compound 11(4.091 g, 23.90 mmol, 77% yield) as a pale yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ(ppm): 9.16 (dd, J=2.2, 0.8 Hz, 1H), 8.57 (dd, J=4.7, 1.6Hz 1H), 8.33-8.28 (m, 1H), 7.54-7.44 (m, 2H), 7.14 (dd, J=7.3, 0.5 Hz,1H), 6.49 (dd, J=8.2, 0.4 Hz 1H), 6.12 (bs, 2H).

Step 2: Methyl 4-([2,3′]bipyridinyl-6-ylaminomethyl)-benzoate (12)

To a stirred suspension of a mixture of 11 (3.00 g, 17.52 mmol), methyl4-formylbenzoate (4.62 g, 28.11 mmol, 1.5-2.0 equiv.) and dibutyl tindichloride 160 mg, 0.53 mmol) in anhydrous THF (15 mL) at roomtemperature was added phenylsilane (2.34 mL, 19.28 mmol) in threeportions over two days. After stirring for 2 to 7 days the reactionmixture was filtered, filtrate was concentrated and purified by flashchromatography on silica gel (MeOH/CH₂Cl₂, 2/98→10/90) to afford thetitle compound 12 (5.50 g, 17.22 mmol, 98% yield) as a pale yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.11 (dd, J=2.3, 0.7 Hz, 1H),8.55 (dd, J=4.7, 1.8 Hz 1H), 8.29-8.24 (m, 1H), 7.93 (d, J=8.4 Hz, 2H),7.57-7.40 (m, 5H), 7.18 (d, J=7.2 Hz, 1H), 6.59 (d, J=8.2 Hz 1H), 4.69(d, J=6.1 Hz, 2H), 3.85 (s, 3H).

Step 3:N-(2-Amino-phenyl)-4-([2,3′]bipyridinyl-6-ylaminomethyl)-benzamide (13a)

The title compound 13a (Example 12) was obtained from 12 as an off-whitesolid in two steps following the same procedure as in Example 2, steps 3and 4 (Scheme 2). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.60 (s, 1H), 9.16(dd, J=2.2, 0.9 Hz, 1H), 8.56 (dd, J=4.8, 1.7 Hz 1H), 8.31 (ddd, J=7.8,2.3, 1.7 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.57-7.48 (m, 3H), 7.46 (ddd,J=8.0, 4.7, 0.8 Hz, 1H), 7.42 (t, J=6.1 Hz, 1H), 7.19 (dd, J=7.2, 0.6Hz, 1H), 7.17 (dd, J=7.3, 1.0 Hz, 1H), 6.98 (td, J=7.5, 1.4, 1H), 6.79(dd, J=7.8, 1.4 Hz 1H), 6.65-6.57 (m, 2H), 4.90 (bs, 2H), 4.69 (d, J=6.1Hz, 2H).

Examples 13-16

Examples 13-16 (compounds 13b-13e) were prepared using the sameprocedures as described for compound 13a, example 12 (scheme 3). TABLE 213b-e

Cmpd Ex Ar Name Characterization 13b 13

N-(2-Amino-phenyl)- 4-[(3-pyridin-3-yl- phenylamino)-methyl]- benzamide¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.57 (s, 1H), 8.73 (dd, J = 2.6, 1.0Hz, 2H), 8.50 (dd, J = 4.8, 1.6 Hz, 1H), 7.93-7.88 (m, 3H), 7.49 (d, J =8.4 Hz, 2H), 7.42 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.14 (q, J = 7.6 Hz,2H), 6.93 (td, J = 8.0, 1.6 Hz, 1H), 6.86-6.81 (m, 2H), 6.74 # (dd, J =8.0, 1.2 Hz, 1H), 6.63-6.52 (m, 3H), 4.86 (s, 2H), 4.43 (d, J = 6.0 Hz,2H). 13c 14

N-(2-Amino-phenyl)- 4-[(4-pyridin-3-yl- phenylamino)-methyl]- benzamide¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.58 (s, 1H), 8.73 (d, J = 2.0 Hz,1H), 8.38 (dd, J =4.4, 1.2 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.90-7.86(m, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.34 (ddd,J = 8.0, 4.8, 0.8 Hz, 1H), 7.12 (d, J = 8.0, 1.2 Hz, 1H), 6.94 # (td, J= 7.6, 1.6 Hz, 1H), 6.75 (dd, J = 8.0, 1.2 Hz, 1H), 6.70-6.63 (m, 3H),6.56 (td, J =7.6, 1.6 Hz, 1H), 4.87 (s, 2H), 4.41 (d, J = 6.4 Hz, 2H).13d 15

N-(2-Amino-phenyl)- 4-([3,3′]bipyridinyl-6- ylaminomethyl)- benzamide ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 9.62 (s, 1H), 8.83 (dd, J = 2.4, 0.7 Hz,1H), 8.48 (dd, J = 4.7, 1.6 Hz 1H), 8.38 (d, J = 2.5 Hz, 1H), 7.99 (ddd,J = 7.9, 2.3, 1.6 Hz, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.82 (dd, J = 8.8,2.5 Hz, 1H), 7.54-7.45 (m, 3H), 7.43 (ddd, J = 7.9, # 4.7, 0.7 Hz, 1H),7.18 (d, J = 7.0 Hz, 1H), 6.99 (td, J = 7.6, 1.6, 1H), 6.79 (dd, J =8.0, 1.4 Hz 1H), 6.68 (d, J = 8.6 Hz, 1H), 6.61 (td, J = 7.5, 1.3 Hz,1H), 4.91 (bs, 2H), 4.65 (d, J = 6.1 Hz, 2H). 13e 16

N-(2-Amino-phenyl)- 4-[(5-pyridin-3-yl- pyrimidin-2-ylamino)-methyl]-benzamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.62 (s, 1H), 8.88(d, J = 2.2 Hz, 1H), 8.72 (bs, 2H), 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 8.15(t, J = 6.5 Hz, 1H), 8.06 (dt,J = 8.0, 2.0 Hz, 1H), 7.94 (d, J = 8.2 Hz,2H), 7.48-7.45 (m, 3H), 7.17 (d, J = 7.6 Hz, 1H), 6.98 (td, J = 7.6, #1.3 Hz, 1H), 6.79 (dd, J = 8.0, 1.2 Hz, 1H), 6.61 (td, J = 7.7, 1.2 Hz,1H), 4.91 (s, 2H), 4.66 (d, J = 6.3 Hz, 2H).

Example 17N-(2-Amino-phenyl)-4-[(4-thiophen-3-yl-pyrimidin-2-ylamino)-methyl]-benzamide.(16a) Step 1: 2-Chloro-4-thiophen-3-yl-pyrimidine (14)

To a solution of 3-thiopheneboronic acid (500 mg, 3.91 mmol) and2,4-dichloropyrimidine (1.16 g, 7.81 mmol) in acetonitrile (20 mL) wasadded a 0.4 M solution of Na₂CO₃ (20 mL) followed by Pd(PPh₃)₄ (450 mg,0.39 mmol). The suspension was degassed and heated at 90° C. for 16 hunder nitrogen, cooled down, concentrated and extracted with EtOAc.Organic layer was successively washed with saturated solution of NH₄Cl,brine, dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on silica gel(EtOAc/CH₂Cl₂: 2/98) to afford the title compound 14 (680 mg, 3.46 mmol,88% yield). ¹H NMR: (400 MHz, CDCl₃) δ (ppm): 8.56 (d, J=5.2 Hz, 1H),8.19 (dd, J=3.2, 1.2 Hz, 1H), 7.66 (dd, J=5.2, 1.2 Hz, 1H), 7.46 (d,J=5.2 Hz, 1H), 7.43 (dd, J=5.2, 2.8 Hz, 1H).

Step 2: Methyl 4-[(4-thiophen-3-yl-pyrimidin-2-ylamino)-methyl]-benzoate(15)

To a solution of 14 (680 mg, 3.46 mmol) and methyl4-(aminomethyl)benzoate (686 mg, 4.51 mmol) in dry 1,4-dioxane (10 mL)was added DIPEA (1.50 mL, 8.65 mmol) and the mixture was heated for 48 hat 130° C. in a sealed tube. Solvents were removed under vacuum and theresidue was triturated with a mixture of EtOAc/Et₂O, to form a solid,which was collected by filtration and dried. This material was purifiedby flash chromatography on silica gel (EtOAc/CH₂Cl₂: 30/70) to affordthe title compound 15 (540 mg, 1.66 mmol, 48% yield). ¹H NMR: (400 MHz,DMSO-d₆) δ (ppm): 8.29-8.23 (m, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.84-7.77(m, 1H), 7.69-7.59 (m, 2H), 7.52-7.43 (m, 2H), 7.03 (d, J=5.2 Hz, 1H),4.60 (d, J=6.4 Hz, 2H), 3.81 (s, 3H).

Steps 3:N-(2-Amino-phenyl)-4-[(4-thiophen-3-yl-pyrimidin-2-ylamino)-methyl]-benzamide(16a)

The title compound 16a (example 17) was obtained from 15 as an off-whitesolid in two steps following the same procedure as in Example 2, steps 3and 4 (Scheme 2). ¹H NMR: (400 MHz, DMSO-d₆) δ (ppm): 9.59 (s, 1H),8.32-8.27 (m, 2H), 7.91 (d, J=8.0 Hz, 2H), 7.83 (t, J=6.4 Hz, 1H), 7.71(d, J=4.8 Hz, 1H), 7.68-7.63 (m, 1H), 7.54-7.44 (m, 2H), 7.15 (d, J=8.0Hz, 1H), 7.06 (d, J=5.2 Hz, 1H), 6.96 (td, J=7.6, 1.6 Hz, 1H), 6.77 (dd,J=8.0, 1.2 Hz, 1H), 6.59 (td, J=7.6, 1.2 Hz, 1H), 4.89 (s, 2H), 4.62 (d,J=6.4 Hz, 2H).

Examples 18-24

Examples 18-24 (compounds 16b-16 h) were prepared using the sameprocedure as described for compound 16a, example 17, (scheme 4). TABLE 316b-h

Cmpd Ex. Ar R Name Characterization 16b 18

H N-(2-Amino phenyl)-4-{[4-(4- methoxy-phenyl)- pyrimidin-2-ylamino]-methyl}- benzamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.56 (s,1H), 8.26 (d, J = 5.2, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.0Hz, 2H), 7.79 (t, J = 6.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.12 (d, J= 7.2 Hz, 1H), 7.09 (d, J = 5.2 Hz, 1H), 7.02 (d, # J = 8.8 Hz, 2H),6.55 (td, J =7.2, 1.2 Hz, 1H), 6.74 (dd, J = 8.0, 1.2 Hz, 1H), 6.56 (t,J = 7.6 Hz, 1H), 4.86 (s, 2H), 4.62 (d, J = 6.0 Hz, 2H), 3.81 (s, 3H).16c 19

H 4-{[4-(3-Acetyl- phenyl)-pyrimidin- 2-ylamino]-methyl}- N-(2-amino-phenyl)-benzamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.55 (s, 1H), 8.58(s, 1H), 8.36 (d, J = 4.8 Hz, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.10-7.98(m, 1H), 8.00 (t, J = 6.0 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.62 (t, J= 7.6 Hz, 1H), 7.47 (bs, 2H), 7.24 (d, J = 5.2 Hz, # 1H), 7.09 (d, J =7.6 Hz, 1H), 6.92 (td, J = 7.6, 1.6 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H),6.54 (t, J =7.6 Hz, 1H), 4.85 (s, 2H), 4.61 (d, J = 6.0 Hz, 2H), 2.63(s, 3H). 16d 20

H N-(2-Amino- phenyl)-4-{[4-(3,4- difluoro-phenyl)- pyrimidin-2-ylamino]-methyl}- benzamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.55 (s,1H), 8.35 (d, J = 5.2, 1H), 8.14-8.04 (m, 1H), 7.99-7.91 (m, 2H), 7.88(d, J = 8.0 Hz, 2H), 7.60-7.38 (m, 3H), 7.19 (d, J = 5.2 Hz, 1H), 7.10(d, J = 8.4 Hz, 1H), 6.92 (td, J = 7.6, 1.6 Hz, 1H), 6.73 # (dd, J =7.6, 1.6 Hz, 1H), 6.55 (t, J = 6.8 Hz, 1H), 4.85 (m, 1H), 4.61 (d, J =4.8 Hz, 2H). 16e 21

H N-(2-Amino- phenyl)-4-{[4-(3- trifluoromethoxy- phenyl)-pyrimidin-2-ylamino]-methyl}- benzamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.56(s, 1H), 8.37 (d, J = 5.2, 1H), 8.12-7.95 (m, 3H), 7.88 (d, J = 8.0 Hz,2H), 7.65-7.57 (m, 1H), 7.53-7.40 (m, 3H), 7.22 (d, J = 5.2 Hz, 1H),7.10 (d, J = 8.0 Hz, 1H), 6.92 (td, J = 7.6, 1.2 Hz, 1H), # 6.73 (dd, J= 8.0, 1.2 Hz, 1H), 6.55 (t, J = 7.2 Hz, 1H), 4.84 (m, 2H), 4.60 (d, J =6.4 Hz, 2H). 16f 22

NH₂ N-(2-Amino phenyl)-4-[(4- amino-6-pyridin-3- yl-pyrimidin-2-ylamino)-methyl]- benzamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.60 (s,1H), 9.06 (d, J = 1.6 Hz, 1H), 8.62 (d, J = 3.7 Hz, 1H), 8.22 (bd, J =7.8 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.56-7.44 (m, 3H), 7.35-7.15 (m,1H), 7.17 (d, J = 7.4 Hz, 1H), 6.98 (td, J = 7.6, 1.5 Hz, 1H), 6.78 #(dd, J = 8.0, 1.4 Hz, 1H), 6.61 (t, J = 7.4 Hz, 1H), 6.65-6.45 (m, 2H),6.30 (s, 1H), 5.04- 4.80 (m, 2H), 4.62 (d, J = 6.3 Hz, 2H). 16g 23

H N-(2-Amino- phenyl)-4-{[4- (3,4,5-trimethoxy- phenyl)-pyrimidin-2-ylamino]-methyl}- benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.64(s, 1H), 8.40 (d, J = 5.3 Hz, 1H), 7.97 (d, J = 7.9 Hz, 3H), 7.56(d, J =7.5 Hz, 2H), 7.41 (s, 2H), 7.28 (d, J = 5.3 Hz, 1H), 7.20 (d, J = 7.5Hz, 1H), 7.02 (dd, J = 7.9, 7.0 Hz, 1H), 6.83 (d, # J = 7.9 Hz, 1H),6.64 (dd, J = 7.5, 7.5 Hz, 1H), 4.92 (s, 2H), 4.67 (d, J = 6.2 Hz, 2H),3.90 (s, 3H), 3.77 ( s, 3H). 16h 24

H N-(2-Amino- phenyl)-4-{[4-(3- fluoro-4-methoxy- phenyl)-pyrimidin-2-ylamino]-methyl}- benzamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.49(s, 1H), 8.22 (d, J = 5.1 Hz, 1H), 7.80 (m, 5H), 7.39 (d, J = 6.3 Hz,2H), 7.18 (t, J = 8.4 Hz, 1H), 7.06 (m, 2H), 6.86 (m, 1H), 6.67 (m, 1H),6.49 (m, 1H), 4.78 (s, 2H), 4.54 (d, J = 5.9 Hz, 2H), 3.82 (s, 3H).

Example 25N-(2-Amino-phenyl)-4-({4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrimidin-2-ylamino}-methyl)-benzamide(22a) Step 1: 2-Chloro-4-(4-methoxy-phenyl)-pyrimidine (17)

To a solution of 4-methoxyphenylboronic acid (3.0 g, 19.7 mmol) and2,4-dichloropyrimidine (5.9 g, 39.0 mmol) in dry acetonitrile (120 mL)was added a 0.4 M solution of Na₂CO₃ (120 mL) followed by Pd(PPh₃)₄ (400mg, 0.35 mmol). The suspension was degassed and heated at 90° C. for 16h, cooled down and concentrated to produce a precipitate which wascollected by filtration, washed with water, dried and purified by flashchromatography on silica gel (EtOAc/CH₂Cl₂: 5/95) to afford the titlecompound 17 (4.25 g, 19.3 mmol, 97% yield).

Step 2: 4-(2-Chloro-pyrimidin-4-yl)-phenol (18)

To a solution of 17 (3.7 g, 16.8 mmol) in dry dichloromethane (42 mL) at0° C. was added boron tribromide (3.17 mL, 33.5 mmol). The mixture wasstirred vigorously at room temperature for 16 h, cooled down to 0° C.Ice-water was poured-in and the stirring was continued for 30 min. Thereaction mixture was concentrated to form a precipitate which wascollected by filtration, washed with water, dried and purified by flashchromatography on silica gel (MeOH/CH₂Cl₂: 2/98) to afford the titlecompound 18 (3.28 g, 15.9 mmol, 94% yield). ¹H NMR: (400 MHz, DMSO-d₆) δ(ppm): 10.26 (s, 1H), 8.66 (d, J=5.6 Hz, 1H), 8.05 (td, J=8.4, 1.6 Hz,2H), 7.96 (d, J=5.6 Hz, 1H), 6.90 (td, J=8.4, 1.6 Hz, 2H).

Step 3: 4-{2-[4-(2-Chloro-pyrimidin-4-yl)-phenoxy]-ethyl}-morpholine(19)

To a solution of 18 (1.8 g, 8.71 mmol) in acetone (80 mL) were added4-(2-chloroethyl)morpholine hydrochloride (1.95 g, 10.5 mmol), potassiumiodide (360 mg, 2.2 mmol) and potassium carbonate (6.0 g, 44.0 mmol),respectively. The reaction mixture was refluxed for 16 h andconcentrated. The residue was diluted with water and the aqueous phasewas extracted twice with EtOAc. The combined organic extracts were driedover anhydrous Na₂SO₄, filtered and concentrated to form a residue waspurified by flash chromatography on silica gel (EtOAc/CH₂Cl₂, 50/50 toMeOH/CH₂Cl₂: 2/98) to afford the title compound 19 (2.7 g, 8.4 mmol, 96%yield).

Step 4: Methyl4-({4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrimidin-2-ylamino}-methyl)-benzoate(20)

To a solution of 19 (2.7 g, 8.4 mmol) and methyl 4-(aminomethyl)benzoatehydrochloride (2.7 g, 13.5 mmol) in dry toluene (33 mL) was added cesiumcarbonate (8.2 g, 25.3 mmol) followed by Pd₂(dba)₃ (464 mg, 0.51 mmol)and rac-BINAP (473 mg, 0.76 mmol). The solution was degassed and heatedat 100° C. for 16 h. The reaction mixture was partitioned between waterand EtOAc and the phases were separated. The organic layer wassuccessively washed with brine, dried over anhydrous Na₂SO₄, filteredand concentrated to form a residue which was purified by flashchromatography on silica gel (MeOH/CH₂Cl₂: 2/98) to afford the titlecompound 20 (1.9 g, 4.2 mmol, 50% yield).

Step 5:4-({4-[4-(2-Morpholin-4-yl-ethoxy)-phenyl]-pyrimidin-2-ylamino}-methyl)-benzoicacid (21)

To a solution of 20 (1.9 g, 4.2 mmol) in a mixture of THF (8 mL), MeOH(8 mL) and water (4 mL) was added NaOH (373 mg, 9.3 mmol). The mixturewas heated at 40° C. for 16 h, then acidified to pH 6 by adding 1N HCl,concentrated, and dried under high vacuum to afford the title compound21, which was used without further purification.

Step 6:N-(2-Amino-phenyl)-4-({4-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrimidin-2-ylamino}-methyl)-benzamide(22a)

To a solution of 21 (crude from the previous step) in dry acetonitrile(50 mL) was added 1,2-phenylenediamine (1.83 g, 16.9 mmol) followed byEt₃N (2.65 mL, 19.0 mmol), HOBt.H₂O (1.03 g, 7.6 mmol) and EDCI.HCl(1.62 g, 8.5 mmol). The mixture was stirred at room temperature for 72h, filtered to remove salts and filtrate was concentrated to form aresidue, which was purified by flash chromatography on silica gel(MeOH/CH₂Cl₂: 2/98 to 5/95). Trituration of this material with a mixtureof EtOAc/CH₂Cl₂, allowed affording the title compound 22a (696 mg, 1.3mmol, 31% yield over 2 steps) as a white solid. ¹H NMR: (400 MHz,DMSO-d₆) δ (ppm): 9.55 (s, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.00 (d, J=8.4Hz, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.77 (t, J=6.4 Hz, 1H), 7.44 (d, J=7.2Hz, 2H), 7.11 (d, J=7.6 Hz, 1H), 7.07 (d, J=5.2 Hz, 1H), 7.01 (d, J=8.4Hz, 2H), 6.92 (td, J=7.6, 1.6 Hz, 1H), 6.73 (dd, J=8.0, 1.6 Hz, 1H),6.55 (td, J=7.4, 1.2 Hz, 1H), 4.85 (s, 2H), 4.61 (d, J=5.6 Hz, 2H), 4.13(t, J=5.6 Hz, 2H), 3.55 (t, J=4.4 Hz, 4H), 2.68 (t, J=5.6 Hz, 2H), 2.45(t, J=4.4 Hz, 4H).

Example 26N-(2-Amino-phenyl)-4-({4-[3-(2-dimethylamino-ethoxy)-phenyl]-pyrimidin-2-ylamino}-methyl)-benzamidehydrochloride (22b)

The title compound 22b was obtained in 6 steps following the sameprocedure as in example 25, steps 1-6 (Scheme 5) starting from3-methoxyphenylboronic acid and using 2-(dimethylamine)ethyl chloridehydrochloride as the alkylating reagent in step 3. The compound wasobtained as the hydrochloride salt by solubilizing it in a mixture ofMeOH and EtOAc and by adding in a solution of 1N HCl in Et₂O. The whiteprecipitate was filtered off, washed with EtOAc and dried under highvacuum. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.31 (d, J=5.2 Hz, 1H), 7.91(d, J=7.6 Hz, 2H), 7.50 (d, J=7.6 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.32(t, J=8.0 Hz, 1H), 7.34-7.28 (m, 1H), 7.05 (td, J=7.6, 1.6 Hz, 1H),7.00-6.96 (m, 1H), 6.97 (d, J=4.8 Hz, 1H), 6.82-6.77 (m, 2H), 6.04 (bs,1H), 4.74 (d, J=6.0 Hz, 2H), 4.11 (t, J=5.2 Hz, 2H), 2.94 (t, J=5.2 Hz,2H), 2.45 (s, 6H).

Example 27N-(2-Amino-phenyl)-4-({4-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrimidin-2-ylamino}-methyl)-benzamide(22c)

The title compound 22c was obtained in 6 steps following the sameprocedure as in example 25 (steps 1-6, scheme 5) starting from3-methoxyphenylboronic acid and using 4-(2-chloroethyl)morpholinehydrochloride as the alkylating reagent in step 3. ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 9.54 (s, 1H), 8.31 (d, J=5.2 Hz, 1H), 7.92-7.83 (m,3H), 7.65-7.52 (m, 2H), 7.45 (d, J=6.4 Hz, 2H), 7.35 (t, J=8.4 Hz, 1H),7.15 (d, J=5.2 Hz, 1H), 7.11 (d, J=6.8 Hz, 1H), 7.03 (d, J=6.8 Hz, 1H),6.92 (td, J=7.6, 1.2 Hz, 1H), 6.73 (dd, J=7.6, 1.2 Hz, 1H), 6.55 (t,J=6.8 Hz, 1H), 4.85 (s, 2H), 4.61 (d, J=6.0 Hz, 2H), 4.14-4.06 (m, 2H),3.55 (t, J=4.8 Hz, 4H), 2.70 (t, J=5.6 Hz, 2H), 2.50-2.44 (m, 4H).

Example 28N-(2-Amino-phenyl)-4-({4-[4-(2-dimethylamino-ethoxy)-phenyl]-pyrimidin-2-ylamino}-methyl)-benzamide(22d)

The title compound 22d was obtained in 6 steps following the sameprocedure as in example 25, (steps 1-6, scheme 5) starting from4-methoxyphenylboronic acid and using 2-(dimethylamine)ethyl chloridehydrochloride as the alkylating reagent in step 3. ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 10.52-10.35 (bs, 1H), 9.97 (s, 1H), 8.29 (d, J=5.2 Hz,1H), 8.06 (d, J=8.8 Hz, 2H), 7.96 (d, J=8.0 Hz, 2H), 8.10-7.85 (m, 1H),7.52-7.40 (m, 2H), 7.31 (t, J=7.6 Hz, 1H), 7.20-7.00 (m, 5H), 6.96-6.88(m, 1H), 4.70-4.58 (m, 2H), 4.45-4.38 (t, J=4.8 Hz, 2H), 3.54-3.46 (m,2H), 2.83 (s, 6H).

Example 29N-(2-Amino-phenyl)-4-[(4-pyrazin-2-yl-pyrimidin-2-ylamino)-methyl]-benzamide(26a) Step 1: 3-Dimethylamino-1-pyrazin-2-yl-propenone (23a)

A solution of acetylpyrazine (5 g, 40.9 mmol) in N,N-dimethylformamidedimethyl acetal (10.9 mL, 81.8 mmol) and Et₃N (5.7 mL) was heated at110° C. for 16 h. The heating was stopped and a precipitate was formedwhile it was allowed to cool down to room temperature. The suspensionwas diluted with tert-butyl methyl ether; the solid was separated byfiltration and washed with tert-butyl methyl ether. This material wastriturated with the same solvent, filtered off and dried to afford thetitle compound 23a as a yellow solid (5.9 g, 33.3 mmol, 81% yield). ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 9.09 (s, 1H), 8.73 (d, J=2.4 Hz, 1H),8.66 (dd, J=2.4, 1.6 Hz, 1H), 7.84 (d, J=12.4 Hz, 1H), 6.30-6.20 (m,1H), 3.19 (s, 3H), 2.93 (s, 3H).

Step 2: 4-guanidinomethyl-benzoic acid methyl ester dihydrate (24)

To a solution of methyl 4-(aminomethyl)benzoate hydrochloride (5 g) indry ethanol (25 mL) was added 1H-pyrazole-1-carboxamidine hydrochloride(4.4 g) followed by DIPEA (13.0 mL) and the mixture was refluxed for 3h. Ethanol was removed under vacuum. To the remaining viscous oilsaturated solution of NaHCO₃ (50 mL) was slowly added under vigorousstirring followed by addition of 300 ml water (resultant pH 9). A whitesolid is formed and stirring was continued for 1 h. This material wasfiltered off, washed with water (200 mL) and tert-butyl methyl ether (50mL), and dried to give the title compound 24 as a white powder (4.7 g,91%). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.91 (d, J=8.0 Hz, 2H), 7.39(d, J=8.0 Hz, 2H), 4.39 (s, 2H), 3.83 (s, 3H), 3.80-2.80 [m, 4H+2H₂O(determined by elemental analysis]).

Step 3 Method A: 4-[(4-Pyrazin-2-yl-pyrimidin-2-ylamino)-methyl]-benzoicacid (25a)

A suspension of 24 (6.2 g, 25.4 mmol) and 23a (3.0 g, 16.9 mmol) inanhydrous methanol (40 mL) was stirred and heated to reflux for 10 min,then a solution of sodium methoxide 95% (3.65 g, 67.6 mmol) in methanol(40 mL) was slowly added. After refluxing for 24 h, 20 mL of 2.5N NaOHin water were added and the refluxing was maintained for additional 24h. The mixture was allowed to cool to the room temperature methanol wasremoved under reduced pressure, 100 mL of water were added and theresultant mixture was extracted with AcOEt. The aqueous phase wasseparated and acidified to pH 5-6 with 2N HCl to form a precipitatewhich was collected by filtration, rinsed with water and dried to affordthe desired carboxylic acid 25a (4.55 g, 14.8 mmol, 87%) as a whitesolid.

Step 4:N-(2-Amino-phenyl)-4-[(4-pyrazin-2-yl-pyrimidin-2-ylamino)-methyl]-benzamide(26a)

To a solution of 25a (1 g, 3.3 mmol) in dry acetonitrile (35 mL) wasadded 1,2-phenylenediamine (0.88 g, 8.1 mmol) followed by Et₃N (2.7 mL,19.1 mmol), HOBt.H₂O (803 mg, 5.9 mmol) and EDCI.HCl (1.89 g, 9.9 mmol).The mixture was stirred at room temperature for 16 h to form asuspension which was collected by filtration, washed successively withMeCN, water and again MeCN, triturated with MeOH, filtered and dried toafford the title compound 26a (730 mg, 1.84 mmol, 55% yield). ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 9.57 (s, 1H), 9.43 (s, 1H), 8.75 (d, J=4.8Hz, 2H), 8.49 (d, J=5.2 Hz, 1H), 8.11 (t, J=5.2 Hz, 1H), 7.91 (d, J=8.4Hz, 2H), 7.59-7.37 (m, 2H), 7.44 (d, J=5.2 Hz, 1H), 7.12 (d, J=7.6 Hz,1H), 6.94 (td, J=7.6, 1.6 Hz, 1H), 6.75 (dd, J=8.0, 1.2 Hz, 1H), 6.57(t, J=7.2 Hz, 1H), 4.86 (s, 2H), 4.66 (d, J=5.2 Hz, 2H).

Example 30N-(2-Amino-phenyl)-4-[(4-pyridin-2-yl-pyrimidin-2-ylamino)-methyl]-benzamide(26b)

Compound 26b was prepared following the same procedure as in example 29,steps 1, 2 and 4 (scheme 6). For the step 3, method B was used:

Step 3 Method B: 4-[(4-Pyridin-2-yl-pyrimidin-2-ylamino)-methyl]-benzoicacid (25b)

To a solution of 24 (0.85 g, 4.83 mmol) and3-dimethylamino-1-pyridin-2-yl-propenone 23b (1.0 g, 4.83 mmol) ini-PrOH (20 mL) were added molecular sieves (0.2 g, 4 Å, powder, >5 μm).The reaction mixture was refluxed for 16 h then the cloudy solution wasfiltered through a celite pad. The mother liquor was concentrated to thehalf of its volume, a solid was formed which was collected by filtrationand dried to give a pale yellow crystalline material (0.62 g, 1.94 mmol,40% yield). This compound (0.456 g, 1.43 mmol) was dissolved in amixture of THF (3 mL), MeOH (3 mL) and water (1.5 mL), then NaOH (0.125g, 3.14 mmol) was added and the reaction mixture was stirred at 40° C.for 16 h, cooled down to the room temperature, acidified to pH 5-6 byadding 1N HCl (3.2 mL), and concentrated to remove the organic solvents.A precipitate was formed which was collected by filtration, washed withwater and dried afford the title compound 25b (0.542 g, 1.37 mmol, 96%yield).

Examples 31-33

Examples 31-33 (compounds 26b-26d) were prepared using the sameprocedure as described for compound 26a (example 29, scheme 6). TABLE 4

Cmpd Ex Ar Name Characterization 26b 31

N-(2-Amino- phenyl)-4-[(4- pyridin-2-yl- pyrimidin-2- ylamino)-methyl]-benzamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.55 (s, 1H), 8.65 (d, J =4.3 Hz, 1H), 8.41 (d, J = 4.7 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.94(m, 2H), 7.88 (d, J = 8.2 Hz, 2H), 7.46-7.50 (m, 4H), 7.11 (d, J = 7.4Hz, 1H), 6.92 (m, 1H), 6.73 (dd, J = 7.8, 1.2 Hz, 1H), 6.55 # (m, 1H),4.84 (s, 2H), 4.64 (d, J = 5.9 Hz, 2H). 26c 32

N-(2-Amino- phenyl)-4-[(4- thiazol-2-yl- pyrimidin-2- ylamino)-methyl]-benzamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.56 (s, 1H), 8.43 (d, J =5.2, 1H), 8.18-8.08 (m, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.90 (d, J =8.4 Hz, 2H), 7.56-7.37 (m, 2H), 7.27-7.18 (m, 1H), 7.12 (d, J = 7.6 Hz,1H), 6.94 (td, J = 7.6, 1.6 Hz, 1H), 6.74 (dd, J = 8.0, 1.2 HZ, # 1H),6.56 (t, J = 7.2 Hz, 1H), 4.86 (s, 2H), 4.59 (d, J = 6.8 Hz, 2H). 26d 33

N-(2-Amino- phenyl)-4-{[4-(6- chloro-pyridin-3- yl)-pyrimidin-2-ylamino]-methyl}- benzamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.57 (s,1H), 9.06 (s, 1H), 8.46 (m, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.05 (m, 1H),7.90 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.47 (m, 2H), 7.27(d, J = 5.1 Hz, 1H), 7.12 (d, J = 7.4 Hz, 1H), 6.94 (m, 1H), 6.75 # (dd,J =8.0, 1.4 Hz, 1H), 6.57 (m, 1H), 4.87 (s, 2H), 4.64 (d, J = 6.1 Hz,2H).

Example 345-{2-[4-(2-Amino-phenylcarbamoyl)-benzylamino]-pyrimidin-4-yl}-pyridine-2-carboxylicacid dimethylamide (29a) Step 1: 6-Dimethylcarbamoyl-nicotinic acid (27)

To a suspension of pyridine-2,5-dicarboxylic acid dimethyl ester (10.1g, 51.6 mmol) and MgBr₂ (4.75 g, 25.8 mmol) in THF (200 mL) was addeddrop-wise a solution of dimethylamine (51.6 mL, 103.2 mmol, 2N in THF)at room temperature under nitrogen over a period of 10 min. The reactionmixture was stirred overnight and quenched with 1N HCl (52 mL) and H₂O(50 mL), extracted with EtOAc (200 mL×3). The organic phase was washedwith brine, dried over Na₂SO₄, filtered and concentrated. The cruderesidue was dissolved in a mixture of DMF (10 mL), AcOEt (50 mL), MeOH(20 mL) and DCM (50 mL), the formed solution was partially evaporated toproduce a crystalline material, which was removed by filtration. Themother liquor was collected and evaporated to form a solid, which wasdissolved in a mixture of THF (67 mL) and MeOH (67 mL). To this solutionNaOH (2.95 g, 73.7 mmol) in H₂O (33.5 mL) was added. The reactionmixture was heated at 40° C. for few hours, acidified (pH 3) to form asolid precipitate, which was collected by filtration and dried to affordthe title compound 27 (4.937 g, 50% yield over two steps).

Step 2: 5-Acetyl-pyridine-2-carboxylic acid dimethylamide (28)

A suspension of 27 (4.937 g, 25.41 mmol), SOCl₂ (2.41 mL, 33 mmol) andDMF (0.9 mL, 5.1 mmol) in CH₂Cl₂ (51 mL) was refluxed for 3 h. Thereaction mixture was cooled to room temperature and evaporated todryness. The residue was suspended in toluene and Et₃N (4.25 mL, 30.5mmol) was added. The resulting suspension was cannulated to a stirredand pre-formed suspension of dimethyl malonate (3.49 mL, 30.5 mmol),MgCl₂ (1.742 g, 18.3 mmol), Et₃N (10.2 mL, 73.2 mmol) in toluene (25 mL)over 2 hours. The resulting reaction mixture was stirred overnight andquenched with 1N HCl (50 mL) and water (50 mL) and extracted with EtOAc(200 mL×3). The combined organic layer was washed with brine (100 mL),dried over Na₂SO₄ and filtered. The filtrate was evaporated to drynessto give brown oil (5.21 g) which was dissolved in DMSO (15.4 mL) and H₂O(0.62 mL) and then heated at 130° C. for 2 h, cooled down to roomtemperature, diluted with H₂O (100 mL), extracted with EtOAc. Theorganic layer was washed with brine (100 mL), dried over Na₂SO₄,filtered, and concentrated. The residue was purified by flashchromatography on silica gel (AcOEt/hexane, 70/30 to 100/0) to affordthe title compound 28 (430 mg, 9% yield) as a brown crystalline solid.

Step 3:5-{2-[4-(2-Amino-phenylcarbamoyl)-benzylamino]-pyrimidin-4-yl}-pyridine-2-carboxylicacid dimethylamide (29a)

The title compound 29a (example 34) was obtained from 28 as an off-whitesolid in 4 steps following the same procedure as in example 29, steps 1,3 (Method B) and 4 (Scheme 6). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.57(s, 1H), 9.20 (s, 1H), 8.50 (m, 1H), 8.41 (d, J=4.9 Hz, 1H), 8.04 (m,1H), 7.89 (d, J=7.8 Hz, 2H), 7.65 (m, 1H), 7.46 (m, 2H), 7.29 (d, J=5.1Hz, 1H), 7.11 (d, J=7.4 Hz, 1H), 6.93 (m, 1H), 6.74 (m, 1H), 6.56 (m,1H), 4.86 (s, 2H), 4.65 (m, 2H), 3.02 (s, 3H), 2.94 (s, 3H).

Examples 35N-(2-Amino-phenyl)-4-({4-[6-(morpholine-4-carbonyl)-pyridin-3-yl]-pyrimidin-2-ylamino}-methyl)-benzamide(29b)

The title compound was prepared using the same procedures as describedfor the compound 29a, example 34 (scheme 7). ¹H NMR (400 MHz, DMSO-d₆)δ(ppm): 9.55 (s, 1H), 9.21 (s, 1H), 8.52 (m, 1H), 8.42 (d, J=4.9 Hz,1H), 8.03 (t, J=6.2 Hz, 1H), 7.90 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.0 Hz,1H), 7.47 (m, 2H), 7.29 (d, J=5.1 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 6.93(m, 1H), 6.74 (d, J=7.8 Hz, 1H), 6.56 (m, 1H), 4.85 (s, 2H), 4.64 (d,J=4.9 Hz, 2H), 3.66 (s, 4H), 3.55 (m, 2H), 3.44 (m, 2H).

Example 36N-(2-Amino-phenyl)-4-{[4-(2-methyl-pyridin-3-yl)-pyrimidin-2-ylamino]-methyl}-benzamide(31a) Step 1: 1-(2-Methyl-pyridin-3-yl)-ethanone (30a)

The title compound 30a was obtained from 2-methylnicotinic acid in 92%yield as a brown crystalline solid following the same procedure as inexample 34, (step 2 scheme 7).

Step 2:N-(2-Amino-phenyl)-4-{[4-(2-methyl-pyridin-3-yl)-pyrimidin-2-ylamino]-methyl}-benzamide(31a)

The title compound 31a (example 36) was obtained from 30a as anoff-white solid in 4 steps following the same procedures as in example29, steps 1, 3 (Method B) and 4 (Scheme 6). ¹H NMR (400 MHz, DMSO-d₆)δ(ppm): 9.57 (s, 1H), 8.46 (m, 1H), 8.40 (m, 1H), 7.54 (t, J=6.4 Hz,1H), 7.88 (d, J=8.2 Hz, 2H), 7.75 (d, J=6.3 Hz, 1H), 7.40 (d, J=7.8 Hz,2H), 7.29 (m, 1H), 7.11 (d, J=7.2 Hz, 1H), 6.93 (m, 1H), 6.79 (d, J=4.9Hz, 1H), 6.73 (dd, J=8.0, 1.4 Hz, 1H), 6.55 (m, 1H), 4.86 (s, 2H), 4.48(d, J=6.3 Hz, 2H), 2.66-2.82 (m, 3H).

Example 37N-(2-Amino-phenyl)-4-[(4-pyridin-4-yl-pyrimidin-2-ylamino)-methyl]-benzamide(31b)

The title compound 31b was prepared using the same procedures asdescribed for compound 31a (example 36, scheme 8). ¹H NMR (400 MHz,DMSO-d₆) δ(ppm): 9.56 (s, 1H), 8.70 (d, J=5.3 Hz, 2H), 8.44 (d, J=5.1Hz, 1H), 8.05 (t, J=6.3 Hz, 1H), 7.98 (d, J=6.1 Hz, 2H), 7.90 (d, J=8.2Hz, 2H), 7.47 (bs, 2H), 7.27 (d, J=5.1 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H),6.93 (m, 1H), 6.74 (dd, J=8.0, 1.4 Hz, 1H), 6.56 (m, 1H), 4.86 (s, 2H),4.64 (d, J=5.9 Hz, 2H).

Example 38N-(2-Amino-phenyl)-4-{[4-(6-morpholin-4-yl-pyridin-3-yl)-pyrimidin-2-ylamino]-methyl}-benzamide(34a) Step 1: 1-(6-Chloro-pyridin-3-yl)-ethanone (32)

A suspension of dimethyl malonate (7.8 mL, 68.3 mmol), MgCl₂ (3.872 g,40.7 mmol), Et₃N (19.1 mL, 136.9 mmol) in toluene (15 mL) at roomtemperature under nitrogen was stirred for 2 h. To this mixture asuspension of 6-chloro-nicotinoyl chloride (3.872 g, 40.7 mmol) and Et₃N(4.25 mL, 30.5 mmol) in toluene (46 mL) was added via canula. Theresultant reaction mixture was stirred overnight, quenched with 1N HCl(100 mL) and water (100 mL) and extracted with EtOAc. The organic layerwas washed with brine (100 mL), dried over Na₂SO₄, filtered andconcentrated to give white crystalline material (6.5 g) which wasdissolved in a mixture DMSO (9 mL) and H₂O (0.37 mL), heated at 130° C.for 5 h, cooled down to room temperature and treated with water (10 mL).A precipitate formed which was collected by filtration, rinsed withwater and dried to afford the title compound 32 (1.8 g, 28% yield) aspale yellow crystalline solid.

Step 2: 1-(6-Morpholin-4-yl-pyridin-3-yl)-ethanone (33a)

A solution of 32 (1.25 g, 7.9 mmol) and morpholine (2.20 mL, 25.2 mmol)in EtOH (22 mL) was refluxed for 12 h and then evaporated to dryness.The residue was dissolved in EtOAc (200 mL), washed with saturatedNaHCO₃ (50 mL×2) and brine (50 mL), dried over Na₂SO₄, filtered andevaporated to afford the title compound 33a (1.66 g, quantitative yield)as a pale yellow solid.

Step 3:N-(2-Amino-phenyl)-4-{[4-(6-morpholin-4-yl-pyridin-3-yl)-pyrimidin-2-ylamino]-methyl}-benzamide(34a)

The title compound 34a (example 38) was obtained from 33a as off-whitesolid in 4 steps following the same procedure as in example 29, steps 1,3 (Method B) and 4 (scheme 6). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.57(s, 1H), 8.84 (s, 1H), 8.24 (d, J=5.3 Hz, 1H), 8.18 (m, 1H), 7.90 (d,J=7.3 Hz, 2H), 7.78 (m, 1H), 7.46 (d, J=7.8 Hz, 2H), 7.13 (m, 1H), 7.08(d, J=5.3 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.91 (m, 1H), 6.75 (d, J=7.8Hz, 1H), 5.57 (dd, J=7.2, 7.6 Hz, 1H), 4.87 (s, 2H), 4.61 (d, J=6.1 Hz,2H), 3.70 (m, 4H), 3.56 (m, 4H).

Example 39N-(2-Amino-phenyl)-4-({4-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-pyrimidin-2-ylamino}-methyl)-benzamide(34b)

Title compound 34b was prepared using the same procedure as describedfor compound 34a (example 38, scheme 9). ¹H NMR (400 MHz, DMSO-d₆)δ(ppm): 9.55 (s, 1H), 8.81 (d, J=2.2 Hz, 1H), 8.22 (d, J=5.3 Hz, 1H),8.14 (t, J=8.6 Hz, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.75 (t, J=6.2 Hz, 1H),7.45 (d, J=8.0 Hz, 2H), 7.12 (d, J=7.4 Hz, 1H), 7.05 (d, J=5.3 Hz, 1H),6.93 (m, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.74 (dd, J=8.0, 1.4 Hz, 1H), 6.56(m, 1H), 4.87 (s, 2H), 4.62 (d, J=6.5 Hz, 2H), 3.59 (m, 4H), 2.38 (m,4H), 2.21 (s, 3H).

Example 40N-(2-Amino-phenyl)-4-{[4-(1-oxy-pyridin-3-yl)-pyrimidin-2-ylamino]-methyl}-benzamide(36) Step 1: 1-(1-Oxy-pyridin-3-yl)-ethanone (35)

To a solution of 1-pyridin-3-yl-ethanone (1.00 g, 8.3 mmol) in CH₂Cl₂(8.3 mL) at room temperature was added MTO (methyltrioxorhenium, 113 mg,0.45 mmol) and the reaction mixture was cooled to 15° C. Aqueoussolution of H₂O₂ (30%, 1.13 mL, 9.96 mmol) was added drop wise over aperiod of 20 min and the reaction mixture was stirred for 5 h at 15° C.and cooled to 0° C. Aqueous solution of Na₂S₂O₃ (20%, 20 mL) was added,the mixture was stirred for 10 min, extracted with EtOAc. The aqueouslayer was collected and freeze-dried to form a solid material, which waspurified by flash chromatography on silica gel (MeOH/CH₂Cl₂, 10/90) toafford the title compound 35 (1.3 g, quantitative yield).

Step 2:N-(2-Amino-phenyl)-4-{[4-(1-oxy-pyridin-3-yl)-pyrimidin-2-ylamino]-methyl}-benzamide(36)

The title compound 36 (example 40) was obtained from 35 as a pale yellowsolid in 4 steps following the same procedure as in example 29, steps 1,3 (Method B) and 4 (scheme 6). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.61(s, 1H), 8.81 (bs, 1H), 8.45 (m, 1H), 8.33 (d, J=5.1 Hz, 1H), 8.12 (bs,1H), 7.99 (d, J=7.8 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.55 (t, J=7.0 Hz,1H), 7.50 (m, 2H), 7.29 (d, J=5.1 Hz, 1H), 7.16 (d, J=7.4 Hz, 1H), 6.97(m, 1H), 6.78 (dd, J=8.0, 1.2 Hz, 1H), 6.60 (m, 1H), 4.91 (s, 2H), 4.67(d, J=6.3 Hz, 2H).

Example 41N-(2-Amino-phenyl)-4-({4-[4-(2-dimethylamino-ethoxy)-3-fluoro-phenyl]-pyrimidin-2-ylamino}-methyl)-benzamide(41) Step 1: 4-(4-Benzyloxy-3-fluoro-phenyl)-2-chloro-pyrimidine (37)

The title compound 37 was obtained following the same procedure as inExample 25, step 1 (Scheme 5) starting with4-benzyloxy-3-fluorobenzeneboronic acid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.60 (d, J=5.2 Hz, 1H), 7.90 (dd, J=12.0, 2.4 Hz, 1H), 7.84-7.80(m, 1H), 7.54 (d, J=5.2 Hz, 1H), 7.48-7.32 (m, 5H), 7.10 (t, J=8.4 Hz,1H), 5.24 (s, 2H).

Step 2:4-{[4-(4-Benzyloxy-3-fluoro-phenyl)-pyrimidin-2-ylamino]-methyl}-benzoicacid methyl ester (38)

The title compound 38 was obtained from 37 following the same procedureas in example 17 (step 2, scheme 4). ¹H NMR (400 MHz, CDCl₃) δ (ppm):8.23 (d, J=4.4 Hz, 1H), 7.98 (d, J=8.4 Hz, 2H), 7.78 (dd, J=12.4, 2.0Hz, 1H), 7.67 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.47-7.29 (m, 7H), 7.01 (t,J=8.4 Hz, 1H), 6.88 (d, J=5.6 Hz, 1H), 6.06-5.95 (m, 1H), 5.18 (s, 2H),4.75 (d, J=6.4 Hz, 2H), 3.90 (s, 3H).

Step 3: Methyl4-{[4-(3-fluoro-4-hydroxy-phenyl)-pyrimidin-2-ylamino]-methyl}-benzoate(39)

To a degassed solution of 38 (950 mg, 2.14 mmol) in EtOAc (100 mL) atroom temperature under N₂ was added 10% Pd/C (220 mg, 0.21 mmol). Themixture was hydrogenated for 5 days (1 atm, balloon), filtered through acelite pad, rinsed with MeOH and EtOAc and the filtrate was concentratedto afford the title compound 39 (450 mg, 1.27 mmol, 59% yield).

Step 4: Methyl4-({4-[4-(2-dimethylamino-ethoxy)-3-fluoro-phenyl]-pyrimidin-2-ylamino}-methyl)-benzoate(40)

To a solution of 39 (450 mg, 1.27 mmol) in acetone (25 mL) was added2-(dimethylamino)ethyl chloride hydrochloride (220 mg, 1.53 mmol)followed by potassium iodide (53 mg, 0.32 mmol) and potassium carbonate(878 mg, 6.35 mmol). The reaction mixture was refluxed for 20 h, thensaturated solution of NH₄Cl was added, pH of the mixture was adjusted to8 and acetone was removed under reduced pressure. The formed solid wascollected by filtration, washed with water, dried and purified by flashchromatography on silica gel (MeOH/DCM/NH₄OH: 10/89/1) to afford thetitle compound 40 (525 mg, 1.24 mmol, 97% yield).

Steps 5:N-(2-Amino-phenyl)-4-({4-[4-(2-dimethylamino-ethoxy)-3-fluoro-phenyl]-pyrimidin-2-ylamino}-methyl)-benzamide(41)

The title compound 41 (Example 41) was obtained from 40 as off-whitesolid in two steps following the same procedure as in example 25, steps5 and 6 (scheme 5). ¹H NMR: (400 MHz, DMSO-d₆) δ (ppm): 9.55 (s, 1H),8.27 (d, J=5.2 Hz, 1H), 7.95-7.75 (m, 5H), 7.50-7.35 (m, 2H), 7.25 (t,J=8.0 Hz, 1H), 7.14-7.06 (m, 2H), 6.92 (t, J=7.6 Hz, 1H), 6.72 (d, J=8.0Hz, 1H), 6.54 (t, J=7.6 Hz, 1H), 4.85 (s, 2H), 4.60 (d, J=5.2 Hz, 2H),4.17 (t, J=5.6 Hz, 2H), 2.66 (t, J=5.6 Hz, 2H), 2.21 (s, 6H).

Example 42N-(2-Amino-phenyl)-4-{[4-(4-morpholin-4-ylmethyl-phenyl)-pyrimidin-2-ylamino]-methyl}-benzamide(44) Step 1: 4-(2-Chloro-pyrimidin-4-yl)-benzaldehyde (42)

The title compound 42 was obtained following the same procedure as inexample 25, step 1 (scheme 5), starting with 4-formylphenylboronic acid.¹H NMR: (400 MHz, CDCl₃) δ (ppm): 10.11 (s, 1H), 8.73 (d, J=4.8 Hz, 1H),8.27 (td, J=8.4, 1.6 Hz, 2H), 8.03 (td, J=8.4, 1.6 Hz, 2H), 7.73 (d,J=4.8 Hz, 1H).

Step 2: 4-[4-(2-Chloro-pyrimidin-4-yl)-benzyl]-morpholine (43)

To a solution of 42 (950 mg, 4.35 mmol) and morpholine (455 μL, 5.21mmol) in dry 1,2-dichloroethane (10 mL) at room temperature was addedAcOH (2 drops) followed by NaBH(OAc)₃ (1.1 g, 5.21 mmol) and the mixturewas stirred for 16 h. A solution of 10% K₂CO₃ was added to the reactionmixture followed by dichloromethane and the phases were separated. Theaqueous phase was extracted with CH₂Cl₂ and organic layer was dried overanhydrous Na₂SO₄, filtered to form a residue which was purified by flashchromatography on silica gel (EtOAc/CH₂Cl₂: 20/80) to afford the titlecompound 43 (460 mg, 1.59 mmol, 36% yield).

Steps 3:N-(2-Amino-phenyl)-4-{[4-(4-morpholin-4-ylmethyl-phenyl)-pyrimidin-2-ylamino]-methyl}-benzamide(44)

The title compound 44 was obtained from 43 in three steps following thesame procedure as in example 2, steps 2-4 (scheme 2) and was isolated asthe hydrochloride salt by dissolving it in a mixture of dichloromethaneand EtOAc by adding a 1N HCl in Et₂O solution. The precipitate wasfiltered off, washed with EtOAc and dried under high vacuum. ¹H NMR (400MHz, CDCl₃) δ (ppm): 8.33 (d, J=5.2 Hz, 1H), 8.00-7.93 (m, 1H), 7.95 (d,J=8.0 Hz, 2H), 7.85 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.44 (d,J=8.0 Hz, 2H), 7.29 (d, J=8.4 Hz, 1H), 7.07 (td, J=7.6, 1.2 Hz, 1H),7.00 (d, J=5.2 Hz, 1H), 6.85-6.78 (m, 2H), 5.83 (t, J=6.0 Hz, 1H), 4.78(d, J=6.0 Hz, 2H), 3.74 (t, J=4.0 Hz, 4H), 3.59 (s, 2H), 2.51 (bs, 4H).

Example 43N-(2-Amino-phenyl)-4-[(2-pyridin-3-yl-pyrimidin-4-ylamino)-methyl]-benzamide(47) Step 1: 4-[(2-Chloro-pyrimidin-4-ylamino)-methyl]-benzoic acidmethyl ester (45a) and 4-[(4-chloro-pyrimidin-2-ylamino)-methyl]-benzoicacid methyl ester (45b)

A mixture of 2,4-dichloropyrimidine (4.51 g, 30.3 mmol), methyl4-aminomethyl-benzoate (5.00 g, 30.3 mmol), DIPEA (10.4 mL, 60.6 mmol)in i-PrOH (60 mL) and DMF (40 mL) was refluxed for 5 h. Afterevaporation of the reaction mixture to dryness the residue was purifiedby flash chromatography on silica gel (EtOAc/hexane:40/60→60/40+1% ofEt₃N) to afford the title compounds 45a (3.454 g, 41% yield) and 45b(1.52 g, 14% yield, contaminated with the starting material).

45a, ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.45 (bs, 1H), 7.90-7.94 (m, 3H),7.42 (d, J=8.4 Hz, 2H), 6.53 (d, J=5.9 Hz, 1H), 4.58 (d, J=5.3 Hz, 2H),3.83 (s, 3H)).

45b, ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.27 (t, J=6.5 Hz, 1H), 8.21 (bs,1H), 7.88 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 6.69 (d, J=5.1 Hz,1H), 4.55 (bs, 2H), 3.82 (s, 3H).

Step 2: Methyl 4-[(2-Pyridin-3-yl-pyrimidin-4-ylamino)-methyl]-benzoate(46)

To a suspension of 3-pyridine boroxin (189 mg, 0.60 mmol), 45a (500 mg,1.81 mmol), Pd(OAc)₂ (41 mg, 0.18 mmol) and PPh₃ (95 mg, 0.36 mmol) inDME (1.8 mL) was added a solution of Na₂CO₃ (590 mg dissolved in theminimum quantity of water, 5.60 mmol) at room temperature. The reactionmixture was purged with nitrogen and refluxed for 4 days, evaporated todryness and purified by flash chromatography on silica gel(EtOAc/hexane:30/70+1% of Et₃N) to afford the title compound 46 (152 mg,26% yield) as a pale yellow solid.

Step 3:N-(2-Amino-phenyl)-4-[(2-pyridin-3-yl-pyrimidin-4-ylamino)-methyl]-benzamide(47)

The title compound 47 (example 43) was obtained from 46 as an off-whitesolid in two steps following the same procedure as in Example 34, step 3(reactions 3 and 4) (Scheme 7). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.50(s, 1H), 9.30 (d, J=1.6 Hz, 1H), 8.54 (dd, J=4.7, 1.6 Hz, 1H), 8.46(ddd, J=8.0, 2.0, 2.0 Hz, 1H), 8.11 (dd, J 6.3, 6.1 Hz, 2H), 7.85 (d,J=8.2 Hz, 2H), 7.38-7.43 (m, 3H), 7.05 (m, 1H), 6.86 (m, 1H), 6.67 (dd,J=7.9, 1.5 Hz, 1H), 6.49 (m, 2H), 4.79 (s, 2H), 4.66 (s, 2H).

Example 44N-(2-Amino-phenyl)-4-[(2-morpholin-4-yl-pyrimidin-4-ylamino)-methyl]-benzamide(49) Step 2: Methyl4-[(2-morpholin-4-yl-pyrimidin-4-ylamino)-methyl]-benzoate (48a)

A mixture of 45a (2.50 g, 9.0 mmol), morpholine (0.95 mL, 10.8 mmol) andi-Pr₂NEt (3.12 mmol) in i-PrOH (18.0 mL) in a sealed flask was heated at120° C. overnight and cooled down to room temperature. A precipitate wasformed which was collected by filtration, rinsed with i-PrOH and driedto afford the title compound 48 (2.96 g, quantitative yield).

Step 3:N-(2-Amino-phenyl)-4-[(2-morpholin-4-yl-pyrimidin-4-ylamino)-methyl]-benzamide(49)

The title compound 49 (example 44) was obtained from 48 as an off-whitesolid in two steps following the same procedure as in example 34, step 3(reactions 3 and 4) (scheme 7). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.56(s, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.72 (d, J=5.7 Hz, 1H), 7.56 (bs, 1H),7.40 (d, J=8.2 Hz, 2H), 7.13 (d, J=7.8 Hz, 1H), 6.94 (m, 1H), 6.75 (m,1H), 6.57 (m, 1H), 5.83 (bs, 1H), 4.87 (s, 2H), 4.51 (bs, 2H), 3.56 (s,8H).

Example 45N-(2-Amino-phenyl)-4-{[4-(6-methylsulfanyl-pyridin-3-yl)-pyrimidin-2-ylamino]-methyl}-benzamide(53) Step 1: 5-Bromo-2-methylsulfanyl-pyridine (50)

To a stirred solution of 2,5-dibromopyridine (5.00 g, 21.11 mmol) inanhydrous toluene (300 mL) at −78° C. under nitrogen was slowly added asolution of n-BuLi (10.13 mL, 25.33 mmol, 2.5M in hexanes). After 2 h at−78° C., methyl disulfide (2.47 mL, 27.44 mmol) was added. The reactionmixture was stirred for 1 h at −78° C. and was allowed to warm to roomtemperature, quenched with saturated NH₄Cl to form a two-phase system.The organic layer was separated, washed with sat NH₄C₁, H₂O and brine,dried over anhydrous MgSO₄, filtered and concentrated. The residue waspurified by flash chromatography on silica gel (AcOEt/hexane, 5/95) toafford the title compound 50 (2.74 g, 13.43 mmol, 64% yield) as a paleyellow oily liquid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 8.49 (dd, J=2.3, 0.6Hz, 1H), 7.60 (dd, J=8.5, 2.4 Hz, 1H), 7.09 (dd, J=8.6, 0.8 Hz, 1H),2.57 (s, 3H).

Step 2: 5-(2-methylsulfanyl-pyridinyl)-boronic acid (51)

To a stirred solution of 50 (2.74 g, 13.43 mmol) and triisopropylborate(3.72 mL, 16.11 mmol) in a mixture of anhydrous toluene/THF (20 mL/5 mL)at −40° C. under nitrogen was added dropwise a solution of n-BuLi (6.98mL, 17.45 mmol, 2.5M in hexanes). After stirring for 1 h at −40° C., themixture was allowed to warm to room temperature and quenched with 2NHCl. The resultant suspension was filtered; the precipitate was rinsedwith H₂O and AcOEt. The filtrate was neutralized with 1N NaOH (pH 7) andextracted with AcOEt. The organic layer and the precipitate werecombined, solvent was evaporated and the solid residue was trituratedwith MeCN-MeOH to afford the title compound 51 (1.84 g, 10.88 mmol, 81%yield) as a pale yellow solid.

Step 3:4-{[4-(6-Methylsulfanyl-pyridin-3-yl)-pyrimidin-2-ylamino]-methyl}-benzoicacid (52)

To a degassed stirred suspension of a mixture of 51 (593 mg, 3.51 mmol),45b (500 mg, 1.80 mmol) and solution of Na₂CO₃ (15 mL, 0.4M) inacetonitrile (15 mL) at room temperature Pd(PPh₃)₄ (126 mg, 0.11 mmol)was added. The reaction mixture was heated at 90-95° C. for 24 h undernitrogen. Then, 1M NaOH (amount) was added and the heating was continuedfor additional 2 h. After cooling to the room temperature the reactionmixture was filtered, filtrate was extracted with AcOEt, the aqueouslayer was collected, filtered, concentrated and acidified with 2N HCl(pH at 5-6). A precipitate was formed which was collected by filtrationand dried to afford the title compound 52 (396 mg, 1.12 mmol, 62% yield)as a beige solid.

Step 4:N-(2-Amino-phenyl)-4-{[4-(6-methylsulfanyl-pyridin-3-yl)-pyrimidin-2-ylamino]-methyl}-benzamide(53)

The title compound 53 (example 45) was obtained from 52 as an off-whitesolid in one step following the same procedure as in example 2, step 4(scheme 2). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.60 (s, 1H), 9.12 (d,J=1.8 Hz, 1H), 8.39 (d, J=5.3 Hz 1H), 8.29 (bd, J=8.0 Hz, 1H), 7.98 (t,J=6.4 Hz, 1H), 7.94 (d, J=8.2 Hz, 2H), 7.56-7.38 (m, 3H), 7.24 (d, J=5.1Hz, 1H), 7.17 (d, J=7.0 Hz, 1H), 6.98 (td, J=7.5, 1.4 Hz, 1H), 6.79 (dd,J=7.9, 1.3 Hz 1H), 6.60 (td, J=7.2, 1.2 Hz, 1H), 4.90 (s, 2H), 4.67 (bd,J=6.3 Hz, 2H), 2.60 (s, 3H).

Example 46N-(2-Amino-phenyl)-4-({4-[6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-pyrimidin-2-ylamino}-methyl)-benzamide(58a) Step 1: 2-(5-Bromo-pyridin-2-yl)-propan-2-ol (54a)

To a stirred solution of 2,5-dibromopyridine (2.00 g, 8.44 mmol) inanhydrous toluene (100 mL) at −78° C. under nitrogen was slowly added asolution of n-BuLi (4.05 mL, 10.13 mmol, 2.5M in hexanes). After 2 h at−78° C., acetone (806 μl, 10.98 mmol) was added. After stirring for 1 h,the reaction mixture was allowed to warm to 0° C. and was quenched witha saturated NH₄Cl. A two-phase system was formed; the organic layer wasseparated, washed with saturated NH₄C₁, H₂O and brine, dried overanhydrous MgSO₄, filtered and concentrated. The residue was purified byflash chromatography on silica gel (AcOEt/CH₂Cl₂: 20/80) to afford thetitle compound 54 (1.37 g, 6.34 mmol, 75% yield) as a pale yellow oilyliquid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): ABX System (δ_(A)=7.32,δ_(B)=7.82, δ_(X)=8.58, J_(AB)=8.4 Hz, J_(BX)=2.3 Hz, J_(AX)=0 Hz, 3H),4.47 (bs, 1H), 1.57 (s, 6H).

Step 2: 5-Bromo-2-(1-methoxymethoxy-1-methyl-ethyl)-pyridine: (55)

To a stirred solution of 54 (1.36 g, 6.29 mmol) and i-Pr₂NEt (2.19 mL,12.59 mmol) in anhydrous dichloromethane (20 mL) at 0° C. under nitrogenwas slowly added chloromethyl methyl ether (1.17 mL, 14.63 mmol). After30 min, the reaction mixture was allowed to warm to room temperature,stirred for two days, concentrated and purified by flash chromatographyon silica gel (AcOEt/hexane:5/95) to afford the title compound 55 (1.56g, 6.00 mmol, 95% yield) as a pale yellow oily liquid. ¹H NMR (400 MHz,CDCl₃) δ(ppm): ABX System (δ_(A)=7.50, δ_(B)=7.80, δ_(X)=8.60,J_(AB)=8.4 Hz, J_(BX)=2.4 Hz, J_(AX)=0.8 Hz, 3H), 4.73 (s, 2H), 3.41 (s,3H), 1.64 (s, 6H)).

Step 3: 5-(2-[1-methoxymethoxy-1-methyl-ethyl]-pyridinyl)-boronic acid(56)

To a stirred solution of 55 (2.90 g, 11.15 mmol) and triisopropylborate(3.09 mL, 13.38 mmol) in a mixture of anhydrous toluene/THF (20 mL/5 mL)at −50° C. under nitrogen was added dropwise a solution of n-BuLi (7.87mL, 13.38 mmol, 1.7M in hexanes) over 10 min. After 45 min at −50° C.,the mixture was allowed to warm to room temperature and was quenchedwith 2N HCl (30 mL) at −30° C. After decantation, the pH of the aqueouslayer was adjusted to 7 with 1N NaOH, and extracted with AcOEt. Theextract was evaporated and the residue was dried under vacuum to affordthe title compound 56a (2.33 g, 10.37 mmol, 93% yield) as beige stickyfoam. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): ABX System (δ_(A)=7.55,δ_(B)=8.11, δ_(X)=8.83, J_(AB)=7.8 Hz, J_(BX)=1.8 Hz, J_(AX)=0.9 Hz,3H), 8.32 (s, 2H), 4.68 (s, 2H), 3.31 (s, 3H), 1.56 (s, 6H)).

Step 4:4-({4-[6-(1-Hydroxy-1-methyl-ethyl)-pyridin-3-yl]-pyrimidin-2-ylamino}-methyl)-benzoicacid (57a)

To a degassed stirred suspension of a mixture of 56 (550 mg, 2.44 mmol),45b (510 mg, 1.84 mmol, not pure) and an aqueous solution of Na₂CO₃ (10mL, 0.4M) in acetonitrile (15 mL) at room temperature Pd(PPh₃)₄ (106 mg,0.09 mmol) was added. The reaction mixture was heated at 95-100° C. for24 h under nitrogen, cooled to room temperature, filtered, filtrate wasconcentrated, diluted with water, washed with AcOEt, acidified with 2NHCl (25 mL) and warmed at 60° C. for 4 h. The reaction mixture wasallowed to cool to room temperature and the pH was adjusted to 5-6 with2N NaOH. A precipitate formed which was collected by filtration, rinsedwith water and dried to afford the title compound 57a (303 mg, 0.83mmol, 45% yield) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ(ppm): 12.82 (bs, 1H), 9.20-9.08 (m, 1H), 8.46-8.32 (m, 2H, included at8.40 ppm, d, J=5.1 Hz), 7.98 (t, J=6.2 Hz, 1H), 7.90 (d, J=8.2 Hz, 2H),7.84-7.72 (m, 1H), 7.58-7.42 (m, 2H), 7.25 (d, J=5.1 Hz, 1H), 5.34 (s,1H), 4.67 (d, J=5.7 Hz, 2H), 1.50 (s, 6H).

Step 5:N-(2-Amino-phenyl)-4-({4-[6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-pyrimidin-2-ylamino}-methyl)-benzamide(58a)

The title compound 58a (example 46) was obtained from 57a as off-whitesolid in one step following the same procedure as in Example 2, step 4(Scheme 2). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.60 (s, 1H), 9.15 (d,J=2.0 Hz, 1H), 8.45-8.35 (m, 2H, included at 8.41 ppm, d, J=5.1 Hz),8.00 (t, J=6.4 Hz, 1H), 7.94 (d, J=8.2 Hz, 2H), 7.79 (bd, J=8.2 Hz, 1H),7.58-7.43 (m, 2H), 7.25 (d, J=5.1 Hz, 1H), 7.16 (d, J=7.4 Hz, 1H), 6.98(td, J=7.6, 1.5 Hz, 1H), 6.78 (dd, J=8.0, 1.4 Hz 1H), 6.60 (t, J=7.4 Hz,1H), 5.37 (s, 1H), 4.90 (s, 2H), 4.68 (d, J=5.7 Hz, 2H), 1.50 (s, 6H).

Example 47N-(2-Amino-phenyl)-4-({4-[6-(1-methoxymethoxy-1-methyl-ethyl)-pyridin-3-yl]-pyrimidin-2-ylamino}-methyl)-benzamide(58b)

The title compound 58b (example 47) was obtained from 56a as off-whitesolid in two steps following the same procedures as in example 46, step4 (note: no acid hydrolysis at 60° C.) and 5 (Scheme 15). ¹H NMR (400MHz, DMSO-d₆) δ(ppm): 9.61 (s, 1H), 9.18 (s, 1H), 8.50-8.32 (m, 2H,included at 8.42 ppm, d, J=5.1 Hz), 8.02 (t, J=6.0 Hz, 1H), 7.94 (d,J=8.0 Hz, 2H), 7.72 (bd, J=7.6 Hz, 1H), 7.59-7.42 (m, 2H), 7.26 (d,J=5.1 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 6.98 (td, J=7.6, 1.4 Hz, 1H),6.79 (d, J=7.8 Hz, 1H), 6.60 (t, J=7.4 Hz, 1H), 4.91 (s, 2H), 4.72 (s,2H), 4.68 (d, J=5.3 Hz, 2H), 3.32 (s, 3H), 1.60 (s, 6H).

Example 48N-(2-Amino-phenyl)-4-[(2-methylsulfanyl-6-pyridin-3-yl-pyrimidin-4-ylamino)-methyl]-benzamide(61a) Step 1: Methyl4-[(6-Chloro-2-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-benzoate (59)

A stirred suspension of 4,6-dichloro-2-(methylthio)pyrimidine (657 mg,3.37 mmol) or 4,6-dichloro-2-(R)-pyrimidine, methyl4-(aminomethyl)benzoate.HCl (744 mg, 3.69 mmol) and i-Pr₂NEt (2.34 mL,13.43 mmol) in a mixture of anhydrous THF/DMF (10 mL/2 mL) undernitrogen was heated at 70-80° C. for 24 h. The mixture was allowed tocool down to room temperature, poured into a saturated NaHCO₃ andextracted with AcOEt. The organic layer was washed with water, saturatedNH₄C₁, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The residue was purified by flash chromatography on silicagel (eluent AcOEt/CH₂Cl₂, 30/70, then 40/60) to afford the titlecompound 59a (929 mg, 2.87 mmol, 85% yield) as a beige powder.

Step 2:4-[(2-Methylsulfanyl-6-pyridin-3-yl-pyrimidin-4-ylamino)-methyl]-benzoicacid (60)

To a degassed stirred suspension of a mixture of 59 (925 mg, 2.86 mmol),2,4,6-(3-pyridinyl)-cyclotriboroxane (360 mg, 1.14 mmol) and aqueous ofNa₂CO₃ (20 mL, 0.4M) in acetonitrile (20 mL) at room temperature wasPd(PPh₃)₄ (165 mg, 0.14 mmol) was added. The reaction mixture was heatedat 95° for one to two days under nitrogen. 1M NaOH (5 mL) was added tothe reaction mixture and the heating was maintained for another 1 h. Themixture was allowed to cool to room temperature and filtered. Thefiltrate was extracted with AcOEt, the aqueous layer was separated,concentrated, and acidified with 2N HCl (pH at 5-7). A precipitateformed which was collected by filtration and dried to afford the titlecompound 60 (770 mg, 2.19 mmol, 76% yield) as a beige solid. ¹H NMR (400MHz, DMSO-d₆) δ(ppm): 12.89 (bs 1H), 9.15 (bs, 1H), 8.72-8.64 (m, 1H),8.39-8.20 (m, 2H), 7.93 (d, J=8.4 Hz, 2H), 7.58-7.40 (m, 3H), 6.84 (s,1H), 4.69 (d, J=5.1 Hz 2H), 2.48 (bs, 3H).

Step 3:N-(2-Amino-phenyl)-4-[(2-methylsulfanyl-6-pyridin-3-yl-pyrimidin-4-ylamino)-methyl]-benzamide(61a)

The title compound 61a (Example 48) was obtained from 60 as off-whitesolid in one step following the same procedure as in example 2, step 4(scheme 2). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.64 (s, 1H), 9.16 (bs,1H), 8.68 (dd, J=4.7, 1.6 Hz 1H), 8.45-8.25 (m, 1H), 8.27 (t, J=5.9 Hz,1H), 7.97 (d, J=8.2 Hz, 2H), 7.58-7.42 (m, 3H), 7.17 (d, J=7.6 Hz, 1H),6.98 (td, J=7.5, 1.4 Hz, 1H), 6.85 (s, 1H), 6.79 (dd, J=7.9, 1.1 Hz 1H),6.61 (t, J=7.2 Hz, 1H), 4.92 (s, 2H), 4.69 (bs, 2H), 2.50 (s, 3H).

Examples 49-50

Examples 49, 50 (compounds 61b-c) were prepared using the sameprocedures as described for compound 61a (example 48, scheme 16). TABLE5

Cmpd Ex R Name Characterization 61b 49 H N-(2-Amino- phenyl)-4-[(6-pyridin-3-yl- pyrimidin-4- ylamino)-methyl]- benzamide ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 9.64 (s, 1H), 9.19 (bs, 1H), 8.69 (d, J = 3.7 Hz 1H),8.56 (s, 1H), 8.36 (d, J = 6.3 Hz, 1H), 8.20 (t, J = 6.0 Hz, 1H), 7.96(d, J =8.0 Hz, 2H), 7.52-7.40 (m, 3H), 7.17 (d, J = 7.0 Hz, 1H), 7.13(s, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.79 (d, # J = 7.6 Hz 1H), 6.61 (t, J= 7.5 Hz, 1H), 4.92 (s, 2H), 4.71 (bs, 2H). 61c 50 NH₂ N-(2-Amino-phenyl)-4-[(2-amino- 6-pyridin-3-yl- pyrimidin-4- ylamino)-methyl]-benzamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.63 (s, 1H), 9.08 (d, J =1.8 Hz, 1H), 8.63 (dd, J = 4.7, 1.6 Hz 1H), 8.24 (d, J = 7.8 Hz, 1H),7.96 (d, J = 8.0 Hz, 2H), 7.63 (bs, 1H), 7.54-7.43 (m, 3H), 7.17 (d, J =7.2 Hz, 1H), 6.98 (td, J = 7.6, 1.2 Hz, 1H), 6.79 (d, J = 6.8 # Hz 1H),6.61 (t, J =7.5 Hz, 1H), 6.38 (s, 1H), 6.19 (bs, 2H). 4.92 (s, 2H), 4.65(bs, 2H).

Example 51N-(2-Amino-phenyl)-4-[(6-pyridin-3-yl-pyrazin-2-ylamino)-methyl]-benzamide(63) Step 1: 4-[(6-Chloro-pyrazin-2-ylamino)-methyl]-benzoic acid methylester (62)

A stirred suspension of 2,6-dichloropyrazine (500 mg, 3.36 mmol), methyl4-(aminomethyl)benzoate.HCl (744 mg, 3.69 mmol) and i-Pr₂NEt (2.05 mL,11.75 mmol) in a mixture of anhydrous THF/DMF (10 mL/2 mL) undernitrogen was heated at 90° C. for 24 h. The mixture was allowed to cooldown to room temperature, was poured into saturated aqueous NH₄Cl andextracted with AcOEt. The organic layer was washed with H₂O and brine,dried over anhydrous MgSO₄, filtered and concentrated. The residue waspurified by flash chromatography on silica gel (AcOEt/CH₂Cl₂:20/80→30/70) to afford the title compound 62 (300 mg, 1.08 mmol, 32%yield) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.18(t, J=6.0 Hz, 1H), 7.97 (s, 1H), AB system (δ_(A)=7.95, δ_(B)=7.49,J_(AB)=8.5 Hz, 4H), 7.75 (s, 1H), 4.58 (d, J=5.9 Hz, 2H), 3.87 (s, 3H).

Step 2:N-(2-Amino-phenyl)-4-[(6-pyridin-3-yl-pyrazin-2-ylamino)-methyl]-benzamide(63)

The title compound 63 (example 51) was obtained from 62 as a beigepowder in two steps following the same procedure as in Example 48, steps2 and 3 (Scheme 16). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.62 (s, 1H),9.19 (dd, J=2.3, 0.8 Hz, 1H), 8.62 (dd, J=4.7, 1.6 Hz 1H), 8.40 (s, 1H),8.36 (ddd, J=8.4, 2.0, 2.0 Hz, 1H), 8.06 (s, 1H), 8.01-7.92 (m, 3H),7.54 (d, J=8.2 Hz, 2H), 7.51 (ddd, J=7.8, 4.7, 0.8 Hz, 1H), 7.16 (bd,J=6.7 Hz, 1H), 6.98 (td, J=7.6, 1.5 Hz, 1H), 6.78 (dd, J=8.0, 1.4 Hz1H), 6.60 (td, J=7.5, 1.3 Hz, 1H), 4.91 (s, 2H), 4.71 (d, J=6.1 Hz, 2H).

Example 52N-(2-Amino-phenyl)-4-[(6-morpholin-4-yl-pyridazin-3-ylamino)-methyl]-benzamide(66) Step 1: 4-(6-Chloro-pyridazin-3-yl)-morpholine (64)

A 50 mL flask equipped with a reflux condenser was charged withmorpholine (2.93 mL, 33.5 mmol) and 3,6-dichloropyridazine (5.00 g, 33.5mmol). The mixture was heated at 90° C. for 6 h, the resultant solid waspartitioned between EtOAc, water and saturated NH₄Cl. Organic layer wasseparated, dried over anhydrous Na₂SO₄, filtered, and evaporated toafford the title compound 64 (5.3 g, 26.5 mmol, 79% yield).

Step 2: Methyl4-[(6-morpholin-4-yl-pyridazin-3-ylamino)-methyl]-benzoate (65)

To a solution of 64 (2.0 g, 10.0 mmol) and methyl4-(aminomethyl)benzoate hydrochloride (2.2 g, 11.0 mmol) in i-PrOH (200mL) was added NH₄Cl (2.14 g, 40.0 mmol). The reaction mixture was heatedat 150° C. for 72 h and concentrated. The residue was dissolved in waterand the aqueous phase was extracted with the aqueous phase wasseparated, treated with 1N NaOH (pH 8) and extracted with EtOAc. Theextract was dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on silica gel (MeOH/CH₂Cl₂:2/98 to 5/95) to afford the title compound 65 (270 mg, 0.82 mmol, 8%yield). ¹H NMR: (400 MHz, CDCl₃) δ (ppm): 7.97 (d, J=8.0 Hz, 2H), 7.42(d, J=8.0 Hz, 2H), 6.90 (d, J=9.2 Hz, 1H), 6.69 (d, J=9.2 Hz, 1H),5.16-5.06 (bs, 1H), 4.67 (s, 2H), 3.90 (s, 3H), 3.82 (t, J=4.8 Hz, 4H),3.41 (t, J=4.8 Hz, 4H).

Steps 3:N-(2-Amino-phenyl)-4-[(6-morpholin-4-yl-pyridazin-3-ylamino)-methyl]-benzamide(66)

The title compound 66 (example 52) was obtained from 65 as an off-whitesolid in two steps following the same procedure as in Example 2, steps 3and 4 (Scheme 2). ¹H NMR: (400 MHz, DMSO-d₆) δ (ppm): 9.57 (s, 1H), 7.89(d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.15-7.12 (m, 1H), 7.13 (d,J=9.6 Hz, 1H), 6.94 (t, J=7.6 Hz, 1H), 6.88 (t, J=6.0 Hz, 1H), 6.83 (d,J=9.6 Hz, 1H), 6.75 (dd, J=8.0, 1.2 Hz, 1H), 6.57 (t, J=8.0 Hz, 1H),4.86 (s, 2H), 4.54 (d, J=6.4 Hz, 2H), 3.69 (t, J=4.8 Hz, 4H), 3.24 (t,J=4.8 Hz, 4H).

Example 53N-(2-Amino-phenyl)-4-[2-oxo-2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-benzamide(71) Step 1: 4-Cyanomethyl-benzoic acid (68)

The title compound was obtained according to the procedure described inJ. Med. Chem. 1997, 40, 377-384, starting from 4-chloromethylbenzoicacid (67).

Step 2: 4-Carboxymethyl-benzoic acid methyl ester (69)

The title compound was obtained according to the procedures described inJ. Med. Chem. 1998, 41, 5219-5246, as a beige solid (85% yield). ¹H NMR(DMSO-d₆) δ (ppm): 12.49 (s, 1H), 7.89 (d, J=1.8 Hz, 2H), 7.39 (d, J=8.2Hz, 2H), 3.84 (s, 3H), 3.79 (s, 2H).

Step 3: Methyl4-[2-Oxo-2-(4-pyridin-2-yl-piperazin-1-yl)-ethyl]-benzoate (70)

Following the procedure described in example 1, step 5 (scheme 1) thetitle compound 70 was obtained as a pale yellow solid (70% yield).¹H-NMR (DMSO) δ: 8.36 (d, J=4.7 Hz, 2H), 7.89 (d, J=8.4 Hz, 2H), 7.38(d, J=8.4 Hz, 2H), 6.65 (t, J=4.8 Hz, 1H), 3.87 (s, 2H), 3.83 (s, 3H),3.71-3.66 (m, 4H), 3.60-3.53 (m, 4H).

Step 4:N-(2-Amino-phenyl)-4-[2-oxo-2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-benzamide(71)

Following the procedures described in Example 1 steps 4 and 5 the titlecompound 71 was obtained as a beige solid (225 mg, 69%). ¹H NMR: (DMSO)δ (ppm): 9.62 (s, 1H), 8.36 (d, J=4.7 Hz, 2H), 7.90 (d, J=8.0 Hz, 2H),7.36 (d, J=8.2 Hz, 2H), 7.13 (d, J=6.8 Hz, 1H), 6.95 (td, J=7.5, 1.4 Hz,1H), 6.76 (dd, J=8.0, 1.4 Hz, 1H), 6.70 (t, J=4.8 Hz, 1H), 6.57 (tdd,J=7.6, 1.4 Hz, 1H), 4.90 (s, 2H), 3.87 (s, 2H), 3.72-3.68 (m, 4H),3.62-3.55 (m, 4H).

Example 54N-(2-Amino-phenyl)-4-(5-chloro-6-fluoro-1H-benzoimidazol-2-ylmethyl)-benzamide(74) Step 1:4-[(2-Amino-4-chloro-5-fluoro-phenylcarbamoyl)-methyl]-benzoic acidmethyl ester (72)

Following the procedure described in example 1, step 5 (scheme 1) thetitle compound 72 was obtained as orange oil (69% yield). LRMS: 336.1(calc.), 337.5 (obt.).

Step 2: 4-(5-Chloro-6-fluoro-1H-benzoimidazol-2-ylmethyl)-benzoic acidmethyl ester (73)

Compound 72 (333 mg, 0.99 mmol) was dissolved in AcOH (10 ml) and thesolution was refluxed, for 24 h. AcOH was evaporated and the residue wasdissolved in AcOEt, washed with aqueous NH₄Cl, NaHCO₃ and brine, anddried over MgSO₄. Evaporation of EtOAc provided the title compound 73 asa brownish powder (297 mg, 95%).

¹H NMR (DMSO-d₆) δ (ppm): 7.90 (d, J=1.8 Hz, 2H), 7.88 (d, J=1.9 Hz,1H), 7.66 (d, J=7 Hz, 1H), 7.51 (d, J=9.8 Hz, 2H), 4.26 (s, 2H), 3.32(s, 3H).

LRMS: 318.1 (calc.), 319.4 (obt.)

Step 3:N-(2-Amino-phenyl)-4-(5-chloro-6-fluoro-1H-benzoimidazol-2-ylmethyl)-benzamide(74)

Following the procedures described in example 1, steps 4 and 5 the titlecompound 74 was obtained as a yellow solid (53% yield). ¹H NMR: (DMSO) δ(ppm): 9.59 (s, 1H), 7.91 (d, J=8.0 Hz, 2H), 7.67 (d, J=6.9 Hz, 1H),7.51 (d, J=9.7 Hz, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.13 (d, J=7.2 Hz, 1H),6.74 (td, J=7.6 Hz, 1H), 7.52 (dd, J=4.7, 4.7 Hz, 1H), 6.57 (dd, J=7.0,1.4 Hz, 2H), 4.87 (s, 2H), 4.26 (s, 2H).

Example 55N-(2-Amino-phenyl)-4-(2,4-dioxo-1,4-dihydro-2H-thieno[2,3-d]pyrimidin-3-ylmethyl)-benzamide(77)

The title compound 77 was obtained starting from2-amino-thiophene-3-carboxylic acid methyl ester via the intermediates75 and 76 (scheme 20) following the same procedures described in PatentApplication WO 03/024448 (69% yield). ¹H NMR (DMSO) δ (ppm): 9.59 (s,1H), 7.88 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.18-7.11 (m, 3H),7.45 (bs, 1H), 6.94 (td, J=7.6, 1.6 Hz, 1H), 6.75 (dd, J=7.8, 1.4 Hz,1H), 6.57 (td, J=7.5, 1.4 Hz, 1H), 5.09 (s, 2H), 4.87 (bs, 2H). LRMS:392.1 (calc.), 393.4 (obt.).

Example 56N-(2-Amino-phenyl)-4-[1-(2-dimethylamino-ethyl)-2,4-dioxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-ylmethyl]-benzamide(80)

The title compound 80 was obtained starting from3-amino-thiophene-2-carboxylic acid methyl ester via the intermediates78 and 79 as a yellow solid following the same procedures described inthe Patent Application WO 03/024448. ¹H NMR (DMSO) δ (ppm): 9.60 (s,1H), 8.22 (d, J=5.5 Hz, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.41-7.39 (m, 3H),7.13 (d, J=7.4 Hz, 1H), 6.95 (td, J=7.6, 1.6 Hz, 1H), 6.75 (dd, J=7.8,1.6 Hz, 1H), 6.57 (td, J=7.4, 1.2 Hz, 1H), 5.16 (s, 2H), 4.88 (bs, 2H),4.23 (m, 2H), 2.81 (m, 2H). LRMS: 463.2 (calc.), 464.4 (obt.).

Example 57{5-[4-(2-Amino-phenylcarbamoyl)-benzyl]-3-cyano-4-methyl-thiophen-2-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester (83) Step 1:4-[4-Cyano-3-methyl-5-(2-morpholin-4-yl-ethoxycarbonylamino)-thiophen-2-ylmethyl]-benzoicacid (82)

To a solution of carbonyl diimidazole (207 mg, 1.28 mM) in anhydrous THF(10 ml) hydroxyethyl morpholine (114 μl, 1.28 mM) was added at 5° C.Cooling was removed, the reaction mixture stirred at rt for 1 hr andadded via canula to a solution of4-(5-amino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzoic acid (81, 350mg, 1.28 mM) (described in the Patent Application WO 03/024448) and DBU(382 μl, 2.56 mM) in anhydrous THF (20 ml) at rt. The combined mixturestirred 3 hrs, THF was evaporated and the remaining solid residue wassuspended in water, acidified with conc. HCl (pH 4) and collected byfiltration. Trituration of this material with 25 ml acetone provided thetitle compound 82 (85 mg, 15% yield). LRMS: 429.5 (calc.) 430.4 (found).

Step 2:{5-[4-(2-Amino-phenylcarbamoyl)-benzyl]-3-cyano-4-methyl-thiophen-2-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester (83)

Following the procedure described in example 1, step 5 the titlecompound 83 was obtained as a solid (26% yield). ¹H NMR: (300 MHz,DMSO-d₆, δ (ppm): 9.61 (s, 1H), 7.92 (d, J=7.91, 2H), 7.34 (d, J=7.91,2H), 7.15 (d, J=7.47, 1H), 6.97 (t, J=7.03, 1H), 6.77 (d, J=7.03, 1H),6.59 (t, J=7.47, 1H), 4.88 (brs, 2H), 4.22 (t, J=5.50, 2H), 4.10 (s,2H), 3.55 (t, J=4.40, 4H), 2.56 (t, J=5.50, 2H), 2.43-2.39 (m, 4H), 2.18(s, 3H). LRMS: 519.6 (calc. 520.5 (found).

Example 58N-(2-Amino-phenyl)-4-(4-cyano-5-propionylamino-thiophen-2-ylmethyl)-benzamide(87) Step 1: 4-(3-Oxo-propyl)-benzoic acid methyl ester (84)

The title compound 84 was obtained according to the procedure describedin J. Org. Chem.; 1992; 57(11); 3218-3225, starting from 4-iodobenzoicacid methyl ester.

Step 2: 4-(5-Amino-4-cyano-thiophen-2-ylmethyl)-benzoic acid methylester (85)

To a suspension of sulfur (309 mg, 4.22 mmol) and methyl4-(3-oxo-propyl)benzoate (84) (812 mg, 4.22 mmol) in DMF (4 ml) at 0° C.was slowly added Et₃N (353 μl, 2.53 mmol) at 0° C. The reaction mixturewas stirred 1 h at room temperature and a solution of malononitrile (279mg, 4.22 mmol) in DMF (6 ml) was slowly added. The reaction mixture wasstirred at room temperature for 16 h, poured into 300 ml of ice/water toyield an orange precipitate, which was filtered, rinsed with cold waterand dried to afford the title compound 85 (1.04 g, 90%) as an orangesolid. LRMS: 272.1 (Calc.); 265.0 (found).

Steps 3, 4:N-(2-Amino-phenyl)-4-(4-cyano-5-propionylamino-thiophen-2-ylmethyl)-benzamide(87)

The title compound 87 was obtained starting from the cyano-compound 85via the intermediate 86 as a yellow solid following the same proceduresas described in Patent Application WO 03/024448, for a similar compound(63% yield). ¹H NMR (DMSO) δ (ppm): 11.26 (s, 1H), 9.61 (s, 1H), 7.92(d, J=7.5 Hz, 2H), 7.39 (d, J=7.5 Hz, 2H), 7.15 (d, J=7.5 Hz, 1H), 6.95(s, 2H), 6.77 (d, J=8.0 Hz, 1H), 6.58 (m, 1H), 5.76-5.75 (m, 1H), 4.88(s, 2H), 4.12 (s, 2H), 2.50 (m, 3H), 1.05-1.03 (m, 3H). LRMS: 404.1(calc.), 405.1 (obt.).

Example 59{5-[4-(2-Amino-phenylcarbamoyl)-benzyl]-3-cyano-thiophen-2-yl}-carbamicacid 2-morpholin-4-yl-ethyl ester (89)

The title compound 89 was obtained starting from the cyano compound 85via the intermediate 88 similarly to the compound 87, example 58 (scheme23) as a yellow solid (15% yield). ¹H NMR: (300 MHz, DMSO-d₆, δ (ppm):9.60 (bs, 1H), 7.91 (d, J=7.8 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.13 (d,J=7.8 Hz, 1H), 6.97-6.93 (m, 2H), 6.76 (dd, J=7.8, 1.2 Hz, 1H), 6.58(ddd, J=7.4, 7.4, 1.2 Hz, 1H), 4.89 (bs, 2H), 4.22 (t, J=5.5 Hz, 2H),4.12 (s, 2H), 3.55 (t, J=4.7 Hz, 4H), 2.56 (t, J=5.7 Hz, 2H), 2.41 (m,4H).

Example 604-(5-Amino-4-cyano-thiophen-2-ylmethyl)-N-(2-amino-phenyl)-benzamide(90)

The title compound 90 was obtained starting from the compound 85 as anorange solid following the same procedures described in example 1 steps4 and 5, (67% yield). ¹H NMR: (DMSO) δ (ppm): 9.60 (bs, 1H), 7.90 (d,J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 7.13 (d, J=6.7 Hz, 1H), 7.03 (bs,1H), 6.95 (ddd, J=7.6, 7.6, 1.6 Hz, 1H), 6.76 (dd, J=6.6, 1.6 Hz, 1H),6.58 (ddd, J=7.4, 7.4, 1.7 Hz, 1H), 6.52 (s, 1H), 4.89 (bs, 2H), 3.95(s, 2H). LRMS: 348.1 (Calc.); 349.2 (found).

Example 612-Amino-5-[4-(2-amino-phenylcarbamoyl)-benzyl]-thiophene-3-carboxylicacid amide (92) Step 2:4-(5-Amino-4-carbamoyl-thiophen-2-ylmethyl)-benzoic acid methyl ester(91)

The title compound 91 was obtained as a yellow solid by following thesame procedure as described in Example 58 step 2 (replacingmalononitrile by 2-cyano-acetamide), (88% yield). LRMS: 304.1 (calc.);305.1 (found).

Step 3-4:2-Amino-5-[4-(2-amino-phenylcarbamoyl)-benzyl]-thiophene-3-carboxylicacid amide (92)

The title compound 92 was obtained as an orange solid starting from thecompound 91 and following the same procedures as described in example 1steps 4 and 5 (54% yield). ¹H NMR: (DMSO) δ (ppm): 9.62(s, 1H), 7.90 (d,J=8.2 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.14-7.12 (m, 3H), 6.95 (td,J=7.6, 1.6 Hz, 1H), 6.84(s, 1H), 6.76 (dd, J=7.8, 1.2 Hz, 1H), 6.58 (td,J=7.4, 1.2 Hz, 1H), 4.87 (s, 2H), 3.93 (s, 2H). LRMS: 366.1 (Calc.);367.4 (found).

Example 62 N-(2-Amino-phenyl)-4-(4-cyano-thiophen-2-ylmethyl)-benzamide(94) Step 4: 4-(4-Cyano-thiophen-2-ylmethyl)-benzoic acid (93)

Starting from the cyano compound 85 and following the proceduresdescribed in example 1, step 4 (ester hydrolysis) and a proceduredescribed in Tetrahedron Lett.; 2001; 42(32); 5367-5370 (de-amination)the title compound 93 was obtained as a brown solid (76% yield). LRMS:243.1 (calcd.), 244.3 (found).

Step 5: N-(2-Amino-phenyl)-4-(4-cyano-thiophen-2-ylmethyl)-benzamide(94)

The title compound 94 was obtained as an orange solid starting from thecompound 93 by following the same procedures described in example 1 step5 (41% yield). ¹H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H), 8.38 (d, J=1.4 Hz,1H), 7.92 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 7.33 (d, J=1.4 Hz,1H), 7.13 (d, J=6.8 Hz, 1H), 6.95 (td, J=7.6, 1.6 Hz, 1H), 6.75 (dd,J=8.0, 1.4 Hz, 1H), 6.57 (td, J=7.4, 1.2 Hz, 1H), 4.89 (bs, 2H), 4.27(s, 2H). LRMS: 333.1 (Calc.); 334.4 (found).

Example 634-(3-Amino-4-cyano-pyrazol-1-ylmethyl)-N-(2-amino-phenyl)-benzamide (97)Step 1: 4-(3-Amino-4-cyano-pyrazol-1-ylmethyl)-benzoic acid methyl ester(95)

To a solution of 3-amino-1H-pyrazole-4-carbonitrile (1.211 g, 11.21mmol) in anhydrous DMF (20 ml) K₂CO₃ (5.414 g, 39.24 mmol) was added.The suspension was stirred 5 min at room temperature and treated withp-bromomethylbenzoic acid methyl ester (2.568 g, 11.21 mmol), stirredfor 2.5 hrs at 100° C., cooled and filtered. Filtrate was evaporated toform an oily residue, which was dissolved in a mixture Et₂O-acetone andkept overnight at −10° C. A crystalline material was formed which wastriturated with hot EtOAc, again kept overnight at −10° C. and wascollected by filtration to form the title compound 95 (675 mg, 24%yield). LRMS: 256.3 (calc.), 257.3 (found).

Step 2: 4-(3-Amino-4-cyano-pyrazol-1-ylmethyl)-benzoic acid (96)

To a solution of NaOH (343 mg, 8.58 mmol) in a mixture of water (10 ml)and MeOH (20 ml) the ester 95 (732 mg, 2.86 mmol) was added. Thereaction mixture was refluxed 2 min and stirred for additional 2 hrs atambient temperature. MeOH was removed under reduced pressure andremaining aqueous solution was acidified with conc. HCl (pH 3-4) to forma precipitate which was collected by filtration to afford the titlecompound (96) (640 mg, 92% yield). LRMS: 242.2 (calc.), 241.1 (found).

Step 3:4-(3-Amino-4-cyano-pyrazol-1-ylmethyl)-N-(2-amino-phenyl)-benzamide (97)

The title compound 97 was obtained as a white solid starting from thecompound 96 following the same procedures as described in example 1 step5. Crude product was purified by flash chromatography, eluentMeOH—CH₂Cl₂ (2:23) followed by trituration with CH₂Cl₂, to afford thetitle compound 97 (58% yield). ¹H NMR: (400 MHz, DMSO-d₆, δ (ppm): 9.61(s, 1H), 8.27 (s, 1H), 7.92 (d, J=8.2, 2H), 7.33 (d, J=8.2, 2H), 7.13 (d(dd), J=7.8, 1H), 6.95 (dd, J=1.4 Hz, J=7.8 Hz, 1H), 6.75 (dd, J=1.2 Hz,j=7.8 Hz, 1H), 6.57 (dd, J=1.2 Hz, 7.6 Hz, 1H), 5.60 (s, 2H), 5.16 (s,2H), 4.89 (s, 2H). LRMS: 332.4 (calc.), 333.4 (found).

Example 64 5-(2,4-Dimethoxy-benzylamino)-benzofuran-2-carboxylic acid(2-amino-phenyl)-amide (102) Steps 1-2: 5-Amino-benzofuran-2-carboxylicacid methyl ester (100)

The title compound 100 was obtained following the procedures describedin J. Am. Chem. Soc. 2000, 122, (6382-6394), starting from2-hydroxy-5-nitro-benzaldehyde (98) via the intermediate ester 99 (74%yield).

Steps 3-4: 5-(2,4-Dimethoxy-benzylamino)-benzofuran-2-carboxylic acid(2-amino-phenyl)-amide (102)

The title compound 102 was obtained as a orange solid via theintermediates 100 and 101 by following the same procedures as describedin example 12, step 2 (scheme 3), and example 1, steps 4 and 5(scheme 1) (76 mg, 41%). ¹H NMR: (DMSO) δ (ppm): 9.69 (s, 1H), 7.44 (s,1H), 7.37 (d, J=8.8 Hz, 1H), 7.17-7.15 (m, 2H), 6.96 (td, J=7.5, 1.4 Hz,1H), 6.84 (dd, J=9.0, 2.3 Hz, 1H), 6.76 (dd, J=8.0, 2.3 Hz, 1H), 6.67(d, J=2.3 Hz, 1H), 6.60-6.56 (m, 2H), 6.45 (dd, J=8.2, 2.3 Hz, 1H), 5.94(t, J=6.0 Hz, 1H), 4.92 (s, 2H), 4.15 (d, J=5.7 Hz, 1H), 3.83 (s, 3H),3.73 (s, 3H). LRMS: 417.2 (calc.); 418.5 (obt.).

Example 65N-(2-Amino-phenyl)-4-[5-(3-methoxy-benzyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzamide(105) Step 1.4-[5-(3-Methoxy-benzyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoic acid (104)

To a suspension of 4-(N-hydroxycarbamidoylmethyl)-benzoic acid (103)(described in the Patent Application WO 03/024448) (464 mg, 2.40 mmol)in anhydrous pyridine (10 ml) (3-methoxy-phenyl)-acetyl chloride (418mg, 2.27 mmol) was added and the reaction mixture was refluxed for 3hrs, cooled, quenched with water (10 ml) and evaporated to form a solidresidue. This material was re-dissolved in CH₂Cl₂, decolorized withcharcoal and purified 3 times by flash chromatography with the eluentsbeing CH₂Cl₂-MeOH (19:1), CH₂Cl₂-acetone (19:1, then 9:1) andacetone-hexane (3:2), to afford the title compound 104 (96 mg, 13%).LRMS: 324.3 (calcd.), 323.3 [M−H]⁻ (found).

N-(2-Amino-phenyl)-4-[5-(3-methoxy-benzyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzamide(105)

The title compound 105 was obtained as a white solid following the sameprocedures described in example 1 step 5 (scheme 1). The crude productwas purified twice by flash chromatography, eluents MeOH—CH₂Cl₂ (1:19),then EtOAc—CH₂Cl₂ (1:2), to afford the title compound in 41% yield.LRMS: 414.5 (calcd.), 415.4 [MH]⁺ (found). ¹H NMR: (400 MHz, DMSO-d₆, δ(ppm): 9.61 (s, 1H), 7.91 (d, J=8.22, 2H), 7.41 (d, J=8.22, 2H), 7.25(t, J=7.83, 1H), 7.14 (d, J=6.65, 1H), 6.96 (m, 1H), 6.89-6.84 (m, 3H),6.76 (dd, J=8.02, 1.37, 1H), 6.58 (dt, J=7.63, 1.30, 1H), 4.89 (s, 2H),4.29 (s, 2H), 4.16 (s, 2H), 3.73 (s, 3H).

Example 665-(4-Oxo-4H-thieno[3,2-d]pyrimidin-3-ylmethyl)-benzofuran-2-carboxylicacid (2-amino-phenyl)-amide (111)

The title compound 111 was obtained starting from the compound 106[reacting with 3H-thieno[3,2-d]pyrimidin-4-one (108)] via theintermediate 109, following the procedures described in the PatentApplication WO 03/024448. ¹H NMR: (DMSO) δ (ppm): 9.87 (s, 1H); 8.72 (s,1H); 8.20 (d, J=5.5 Hz, 1H); 7.81 (s, 1H); 7.68 (m, 2H); 7.54 (dd,J=8.6, 1.6 Hz, 1H), 7.42 (d, J=5.5 Hz, 1H); 7.17 (d, J=6.6, 1H); 6.98(dt, J=7.8, 1.6 Hz, 1H); 6.77 (dd, J=8.2, 1.6 Hz, 1H), 6.59 (dt, J=7.4,1.6 Hz, 1H); 5.35 (s, 2H); 4.96 (s, 2H). LRMS: 416.1 (calc.), 417.4(obt.).

Example 675-(4-Oxo-4H-thieno[3,2-d]pyrimidin-3-ylmethyl)-benzo[b]thiophene-2-carboxylicacid (2-amino-phenyl)-amide (112)

The title compound 112 was obtained starting from the compound 107[reacting with 3H-thieno[3,2-d]pyrimidin-4-one (108)] via theintermediate 110, following the procedures described in the PatentApplication WO 03/024448. ¹H NMR: (DMSO) δ (ppm): 9.89 (s, 1H), 8.74 (s,1H), 8.29 (s, 1H), 8.21 (d, J=5.28, 1H), 8.03 (d, J=8.22, 1H), 7.98 (s,1H), 7.51 (dd, J=8.51, 1.67, 1H), 7.43 (d, J=5.28, 1H), 7.17 (dd,J=7.73, 1.27, 1H), 6.99 (m, 1H), 6.79 (dd, J=8.22, 1.37, 1H), 6.60 (dt,J=7.43, 1.37, 1H), 5.38 (s, 2H), 5.00 (s, 2H). LRMS: 432.1 (calc.),433.3 (obt.)

Example 68 Step 5:2-(4-Trifluoromethoxy-benzylamino)-benzothiazole-6-carboxylic acid(2-amino-phenyl)-amide (117) Step 1: 2-Amino-benzothiazole-6-carboxylicacid methyl ester (113)

The title compound was obtained following the procedure described in J.Med. Chem. 1997; 40 (105-111), starting from 4-amino-benzoic acid methylester.

Step 2: 2-Amino-benzothiazole-6-carboxylic acid (114)

The title compound 114 was obtained following the procedure described inexample 1 step 4 (97% yield). ¹H-NMR (DMSO) δ: 12.58 (s, 1H), 8.23 (d,J=1.8 Hz, 1H); 7.85 (s, 2H); 7.78 (dd, J=8.4, 1.8 Hz, 1H); 7.33 (d,J=7.8 Hz, 1H).

Step 3: {2-[(2-Amino-benzothiazole-6-carbonyl)-amino]-phenyl}-carbamicacid tert-butyl ester (115)

The acid 114 (1.80 g, 9.27 mmol) was combined with(2-amino-phenyl)-carbamic acid tert-butyl ester (2.31 g, 11.1 mmol) andBOP (4.91 g, 11.1 mmol) in DMF. To this solution Et₃N (5.16 ml, 37.1mmol) was added and the mixture was stirred overnight at roomtemperature under nitrogen, concentrated in vacuo and purified by flashcolumn chromatography (30% hexane/EtOAc). To further purify the product,the mixture was partitioned between EtOAc and water, organic layer wasseparated, dried over MgSO₄ and evaporated give the title compound 115(1.84 g, 52%). ¹H-NMR (DMSO) δ: 9.72 (s, 1H), 8.66 (m, 1H); 8.22 (d,J=1.8 Hz, 1H); 7.80 (m, 3H); 7.50 (m, 2H); 7.37 (m, 1H); 7.14 (m, 2H);1.44 (s, 9H).

Step 4: 2-(4-Trifluoromethoxy-phenyl)-benzothiazole-6-carboxylic acid(2-aminophenyl)-amide (116)

To a solution of 115 (300 mg, 0.78 mmol),4-(trifluoromethoxy)benzaldehyde (123 μl, 0.86 mmol), and dibutyltindichloride (24 mg, 0.08 mmol) in THF was added phenylsilane (106 μl,0.86 mmol). The mixture was stirred overnight at room temperature undernitrogen, additional aldehyde and phenylsilane were added and thestirring continued until no more starting material was present. The THFwas evaporated off the mixture and the residue was purified by flashcolumn chromatography (EtOAc/hexane 30/70, then 50/50), to give thetitle compound 116 (314 mg, 72%). ¹H-NMR (DMSO) δ: 9.77 (s, 1H), 8.89(t, J=5.7 Hz, 1H); 8.69 (s, 1H); 8.29 (d, J=1.8 Hz, 1H); 7.84 (dd,J=8.4, 1.8 Hz, 1H); 7.50 (m, 5H); 7.37 (d, J=7.8 Hz, 2H); 7.17 (m, 2H);4.69 (d, J=5.7 Hz, 2H); 1.47 (s, 9H).

Step 5: 2-(4-Trifluoromethoxy-benzylamino)-benzothiazole-6-carboxylicacid (2-amino-phenyl)-amide (117)

To a solution of 116 (306 mg, 0.55 mmol) in DCM was added TFA (2.0 ml).This mixture was stirred at room temperature for 4 hours andconcentrated. The residue was dissolved in EtOAc, washed with NaHCO₃,dried over MgSO₄ and concentrated again. The residue was purified byflash column chromatography (30% hexane in EtOAc) to give the titlecompound 117 as a yellow solid (252 mg, 100%). ¹H-NMR (DMSO) δ: 9.56 (s,1H), 8.83 (t, J=5.8 Hz, 1H), 8.30 (d, J=1.8 Hz, 1H); 7.85 (dd, J=8.4,1.6 Hz, 1H); 7.49 (d, J=8.4 Hz, 2H); 7.43 (d, J=8.4 Hz, 1H); 7.34 (d,J=8.4 Hz, 2H); 7.15 (d, J=7.6 Hz. 1H); 6.94 (brt, J=7.8 Hz, 1H); 6.77(d, J=7.8 Hz, 1H); 6.59 (t, J=7.5 Hz, 1H); 4.66 (d, J=5.7 Hz, 2H). LRMS:458.1 (calc.), 459.2 (obt.)

Example 69 6-(3,4-Dimethoxy-benzylamino)-benzooxazole-2-carboxylic acid(2-amino-phenyl)-amide (120) Step 1: 5-Amino-benzooxazole-2-carboxylicacid methyl ester (118)

The title compound 118 was obtained following the procedures describedin J. Am. Chem. Soc. 2000; 122 (6382-6394) starting frombenzooxazole-2-carboxylic acid methyl ester.

Step 2: 5-(3,4-Dimethoxy-benzylamino)-benzooxazole-2-carboxylic acidmethyl ester (119)

The title compound 119 was obtained as a solid following the sameprocedure as described in example 68 step 4 (scheme 28) (90% yield).LRMS: 342.1 (Calc.); 343.4 (found).

Steps 4-5: 6-(3,4-Dimethoxy-benzylamino)-benzooxazole-2-carboxylic acid(2-amino-phenyl)-amide (120)

The title compound 120 was obtained following the procedures describedin example 1, step 5 (scheme 1) (31% yield). ¹H NMR: (DMSO) δ (ppm):10.06 (s, 1H), 7.56 (d, J=8.80, 1H), 7.22 (dd, J=7.83, 1.37, 1H), 7.02(d, J=1.57, 1H), 6.98 (m, 1H), 6.92 (d, J=1.76, 1H), 6.88 (d, J=1.96,1H), 6.86 (d, J=2.35, 1H), 6.82 (d, J=1.96, 1H), 6.78 (dd, J=7.93, 1.27,1H), 6.60 (m, 1H), 4.99 (brs, 2H), 4.28 (d, J=5.48, 2H), 3.76 (s, 3H),3.73 (s, 3H). LRMS: 418 (calc.), 419.5 (obt.).

Example 701-(3,4,5-Trimethoxy-benzyl)-2,3-dihydro-1H-indole-5-carboxylic acid(2-amino-phenyl)-amide (122)

The title compound 122 was obtained following the procedure described inexample 68 step 4 (scheme 28) (to produce the intermediate 121) andprocedures described in example 1, steps 4 and 5 (scheme 1) (33% yield).¹H-NMR (DMSO) δ: 9.29 (s, 1H), 7.71 (dd, J=8.22, 1.77, 1H), 7.66 (brm,1H), 7.12 (dd, J=7.93, 1.47, 1H), 6.93-6.89 (m, 3H), 6.84 (dd, J=8.22,1.96, 1H), 6.75 (dd, J=8.02, 1.37, 1H), 6.65 (d, J=8.41, 1H), 6.57 (dt,J=7.53, 1.30, 1H), 4.82 (s, 2H), 3.73 (s, 6H), 3.41 (t, J=8.51, 2H),2.98 (t, J=8.51, 2H). LRMS: 435.2 (Calc.); 436.5 (found).

Example 71[6-(2-Amino-phenylcarbamoyl)-1-methyl-1H-indol-3-ylmethyl]-(4-morpholin-4-yl-phenyl)-carbamicacid tert-butyl ester (126) Step 1:3-[(4-Morpholin-4-yl-phenylamino)-methyl]-1H-indole-6-carboxylic acidmethyl ester (123)

To a solution of 3-formyl-1H-indole-6-carboxylic acid methyl ester (500mg, 2.46 mmol), 4-morpholinoaniline (482.3 mg, 2.71 mmol) and dibutyltindichloride (76 mg, 0.25 mmol) in THF was added phenylsilane (334 μl,2.71 mmol). The mixture was stirred at room temperature overnight undernitrogen, THF was evaporated off the mixture and the residue waspurified by flash chromatography (hexane/EtOAc, 20/80) to afford thetitle compound 123 (881 mg, 98%). ¹H-NMR (DMSO) δ: 8.00 (d, J=1.0 Hz,1H), 7.70 (d, J=8.2 Hz, 1H); 7.58 (dd, J=8.4, 1.6 Hz, 1H); 7.52 (d,J=2.0 Hz, 1H); 6.70 (d, J=9.0 Hz, 2H); 6.59 (d, J=9.0 Hz, 2H); 5.48 (t,J=5.8 Hz, 1H); 4.31 (d, J=5.7 Hz, 2H); 3.83 (s, 3H); 3.68 (t, J=4.7 Hz,4H); 2.86 (t, J=4.7 Hz, 4H).

Step 2:3-{[tert-Butoxycarbonyl-(4-morpholin-4-yl-phenyl)-amino]-methyl}-1H-indole-6-carboxylicacid methyl ester (124)

To a solution of 123 (689 mg, 1.89 mmol) in THF (100 ml) Et₃N (289 μl,2.08 mmol) was added dropwise. (BOC)₂O was added slowly and the mixturewas stirred at room temperature overnight under nitrogen, THF wasevaporated off and the residue was partitioned between water and CH₂Cl₂.Organic layer was separated, dried over MgSO₄, evaporated to formanother residue which was purified by flash column chromatography(EtOAc/hexane, 7:3) to afford the title compound 124 (692 mg, 79%).¹H-NMR (CDCl₃) δ: 8.24 (m, 1H), 8.09 (m, 1H); 7.76 (dd, J=8.2, 1.4 Hz,1H); 7.55 (d, J=8.8 Hz, 1H); 7.13 (d, J=2.5 Hz, 1H); 6.93 (m, 3H); 4.97(s, 2H); 3.94 (s, 3H); 3.89 (m, 4H); 3.16 (m, 4H); 1.47 (s, 9H).

Step 3:3-{[tert-Butoxycarbonyl-(4-morpholin-4-yl-phenyl)-amino]-methyl}-1-methyl-1H-indole-6-carboxylicacid methyl ester (125)

To a solution of the ester 124 (473 mg, 1.02 mmol) in DMF (15 ml) wasadded 60% NaH (45 mg, 1.12 mmol). The solution was stirred for one hourat room temperature under nitrogen, cooled to 0° C., treated with MeI(170 μl, 1.12 mmol), warmed to room temperature and stirred overnightunder nitrogen. The mixture was partitioned between water and AcOEt,organic layer was collected, dried over MgSO₄ and concentrated in vacuoto yield 454 mg (93%). ¹H-NMR (DMSO) δ: 7.99 (m, 1H), 7.56 (dd, J=1.4,8.2 Hz, 1H); 7.47 (m, 1H); 7.27 (s, 1H); 6.86 (d, J=8.8 Hz, 2H); 6.75(d, J=9.0 Hz, 2H); 4.86 (s, 2H); 3.83 (s, 3H); 3.76 (s, 3H); 3.67 (t,J=4.8 Hz, 4H); 3.01 (t, J=4.8 Hz, 4H); 1.37 (s, 9H).

Steps 4-5:[6-(2-Amino-phenylcarbamoyl)-1-methyl-1H-indol-3-ylmethyl]-(4-morpholin-4-yl-phenyl)-carbamicacid tert-butyl ester (126)

The procedures described in example 1 steps 4 and 5 (scheme 1) werefollowed to afford the title compound 126 as a solid (134 mg, 33%).¹H-NMR (DMSO) δ: 9.59 (s, 1H); 8.06 (s, 1H); 7.61 (dd, J=1.6, 8.4 Hz,1H); 7.48 (m, 1H); 7.21 (s, 1H); 7.15 (dd, J=7.8, 1.4 Hz, 1H); 6.94 (dt,J=7.8, 1.6 Hz, 1H); 6.86 (m, 2H); 6.76 (m, 3H); 6.58 (dt, J=7.4, 1.4 Hz,1H); 4.88 (s, 2H); 4.87 (s, 2H); 3.76 (s, 3H); 3.68 (t, J=4.8 Hz, 4H);3.02 (t, J=4.8 Hz, 4H); 1.39 (s, 9H). LRMS: 556.2 (Calc.); 557.5(found). Scheme 32

Compound Ex X 129 OH 130 OCH₂CH₂Cl 131

132

133

134 72 OH 135 73 OCH₂CH₂Cl 136 74

137 75

138 76

139 77

Example 72N-(2-Amino-phenyl)-4-[(6-hydroxy-benzothiazol-2-ylamino)-methyl]-benzamide(134) Step 1:(2-{4-[(6-Hydroxy-benzothiazol-2-ylamino)-methyl]-benzoylamino}-phenyl)-carbamicacid tert-butyl ester (129)

The title compound 129 was obtained following the same procedure as forthe reductive amination described in Scheme 3, step 2 (example 12)starting from aminothiazole 127 and aldehyde 128 (described in thePatent Application WO 03/024448) (96% yield). ¹H NMR: (acetone-d₆)δ(ppm): 9.60 (s, 1H), 8.25 (bs, 1H), 7.99 (d, J=8.2 Hz, 2H), 7.69 (d,J=7.4 Hz, 1H), 7.61-7.58 (m, 3H), 7.39 (bs, 1H), 7.27 (d, J=8.6 Hz, 1H),7.19 (quint.d, J=7.4, 2.0 Hz, 2H), 7.12 (d, J=2.3 Hz, 1H), 6.79 (dd,J=8.6, 2.7 Hz, 1H), 4.78 (s, 2H), 1.48 (s, 9H). m/z: 491.5 (MH⁺).

Step 2:N-(2-Amino-phenyl)-4-[(6-hydroxy-benzothiazol-2-ylamino)-methyl]-benzamide(134)

The title compound 134 was obtained starting from compound 129 followingthe same procedure as for the Boc cleavage described in scheme 28, step5 (example 68) (53% yield). ¹H NMR: (DMSO-d₆) δ(ppm): 9.58 (s, 1H), 9.12(s, 1H), 8.25 (t, J=6.3 Hz, 1H), 7.91 (d, J=7.8 Hz, 2H), 7.45 (d, J=8.2Hz, 2H), 7.15 (d, J=8.6 Hz, 1H) 7.12 (s, 1H), 7.02 (d, J=2.7 Hz, 1H),6.94 (t, J=6.7 Hz, 1H), 6.75 (dd, J=8.2, 1.2 Hz, 1H), 6.63 (dd, J=8.6,2.3 Hz, 1H), 6.56 (t, J=7.8 Hz, 1H), 4.87 (s, 2H), 4.59 (d, J=5.5 Hz,2H). m/z: 391.2 (MH⁺).

Example 73N-(2-Amino-phenyl)-4-{[6-(2-chloro-ethoxy)-benzothiazol-2-ylamino]-methyl}-benzamide(135) Step 1:[2-(4-{[6-(2-Chloro-ethoxy)-benzothiazol-2-ylamino]-methyl}-benzoylamino)-phenyl]-carbamicacid tert-butyl ester (130)

The title compound 130 was obtained following the procedure described inJ. Med. Chem., 2002, 45 (6), 1300-1312, and using compound 129 asstarting material. (43% yield). ¹H NMR: (DMSO-d₆) δ(ppm): 9.59 (bs, 1H),8.25 (bs, 1H), 7.99 (d, J=8.0 Hz, 2H), 7.69 (dd, J=7.4, 1.4 Hz, 1H),7.60 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.32 (d, J=2.5 Hz, 1H),7.19 (quint.d, J=7.2, 2.3 Hz, 2H), 6.91 (dd, J=8.6, 2.5 Hz, 1H), 4.79(s, 2H), 4.30 (t, J=5.3 Hz, 2H), 3.92 (t, J=5.5 Hz, 3H), 1.48 (s, 9H).m/z: 553.5, 554.5 (M⁺, M+1).

Step 2.N-(2-Amino-phenyl)-4-{[6-(2-chloro-ethoxy)-benzothiazol-2-ylamino]-methyl}-benzamide(135)

The title compound 135 was obtained starting from compound 130 followingthe same procedures as for the Boc cleavage described in scheme 28, step5 (example 68) (48% yield). ¹H NMR: (DMSO-d₆) δ(ppm): 9.59 (s, 1H), 8.39(t, J=5.5 Hz, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.35(d, J=2.5 Hz, 1H), 7.27 (d, J=8.8 Hz, 1H), 7.13 (d, J=6.8 Hz, 1H), 6.94(td, J=8.0, 1.4 Hz, 1H), 6.83 (dd, J=8.8, 6.1 Hz, 1H), 6.75 (dd, J=8.0,1.4 Hz, 1H), 6.57 (t, J=8.6 Hz, 1H), 4.88 (s, 2H), 4.63 (d, J=6.1 Hz,2H), 4.21 (t, J=5.1 Hz, 2H), 3.92 (t, J=5.3 Hz, 2H). mz: 453.4, 455.4(M⁺, M+1).

Example 74N-(2-Amino-phenyl)-4-({6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-benzothiazol-2-ylamino}-methyl)-benzamide(136) Step 1:{2-[4-({6-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-benzothiazol-2-ylamino}-methyl)-benzoylamino]-phenyl}-carbamicacid tert-butyl ester (131)

The title compound 131 was obtained following the procedure described inJ. Med. Chem., 2002, 45, (6), 1300-1312, and using compound 130 asstarting material. (91% yield). ¹H NMR: (Acetone-d₆) δ(ppm): 7.99 (d,J=8.2 Hz, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.59 (d, J=8.6 Hz, 2H), 7.56 (d,J=2.0 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.28 (d, J=2.5 Hz, 1H), 7.21(quint.d, J=7.2, 1.2 Hz, 2H), 7.03-6.93 (m, 1H), 6.87 (dd, J=8.8, 2.7Hz, 1H), 4.79 (s, 2H), 4.11 (t, J=5.9 Hz, 2H), 2.75 (t, J=5.7 Hz, 2H),2.67-2.51 (m, 4H), 2.48-2.38 (m, 4H), 2.21 (s, 3H), 1.49 (s, 9H).

Step 2:N-(2-Amino-phenyl)-4-({6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-benzothiazol-2-ylamino}-methyl)-benzamide(136)

The title compound 136 was obtained starting from compound 131 followingthe same procedures as for the Boc cleavage described in scheme 28, step5 (example 68) (60% yield). ¹H NMR: (CDCl₃) δ(ppm): 7.97 (d, J=7.9 Hz,2H), 7.58 (d, J=7.9 Hz, 2H), 7.51 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.0 Hz,1H), 7.22-7.17 (m, 2H), 6.99-6.92 (m, 3H), 4.78 (s, 2H), 4.20-4.18 (m,2H), 2.97-2.87 (m, 8H), 2.70-2.66 (m, 2H), 2.61 (s, 3H). m/z: 517.5(MH⁺).

Example 75 (2-Morpholin-4-yl-ethyl)-carbamic acid2-[4-(2-amino-phenylcarbamoyl)-benzylamino]-benzothiazol-6-yl ester(137)

Step 1:[2-(4-{[6-(2-Morpholin-4-yl-ethylcarbamoyloxy)-benzothiazol-2-ylamino]-methyl}-benzoylamino)-phenyl]-carbamicacid tert-butyl ester (132)

To a solution of p-nitrophenylchloroformate (171 mg, 0.848 mmol) in THF(15 mL) cooled to −78° C. under N₂ atmosphere was added Et₃N (236 μL,1.70 mmol). Then a suspension of the intermediate 129 (416 mg, 0.848mmol) in THF (4.2 mL) was added via canula. The resulting yellow mixturewas stirred at −78° C. for 1 h and at 0° C. for 1.5 h, heated at 40° C.for 16 h and cooled to r.t. Then, neat 4-(2-aminoethyl)morpholine (119μL, 0.848 mmol) was added and the solution was stirred for 4 h, quenchedby addition of MeOH. It was allowed to stir for 30 min. andconcentrated. The resulting material was purified by flashchromatography using MeOH/DCM (3:97) affording the title compound 132(165 mg, 30% yield). ¹H NMR: (DMSO-d₆) δ(ppm): 9.77 (s, 1H), 8.64 (bs,1H), 8.56 (t, J=5.9 Hz, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.60 (t, J=5.9 Hz,1H), 7.50 (d, J=8.0 Hz, 2H), 7.50-7.48 (m, 2H), 7.45 (d, J=2.3 Hz, 1H),7.30 (d, J=8.8 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H),6.90 (dd, J=8.2, 2.0 Hz, 1H), 4.67 (d, J=6.0 Hz, 2H), 3.56 (t, J=4.1 Hz,4H), 3.31 (t, J=6.1 Hz, 2H), 3.16 (q, J=6.1 Hz, 2H), 2.39 (t, J=6.8 Hz,4H), 1.42 (s, 9H). m/z: 647.7 (MH⁺).

Step 2: (2-Morpholin-4-yl-ethyl)-carbamic acid2-[4-(2-amino-phenylcarbamoyl)-benzylamino]-benzothiazol-6-yl ester(137)

The title compound 137 was obtained starting from compound 132 followingthe same procedure as for the Boc cleavage described in scheme 28, step5 (example 68) (55% yield). ¹H NMR: (DMSO-d₆): ¹H NMR: (DMSO-d₆): 9.60(s, 1H), 8.56 (t, J=6.3 Hz, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.61 (t, J=5.5Hz, 1H), 7.47 (d, J=7.8 Hz, 2H), 7.46 (d, J=2.3 Hz, 1H), 7.31 (d, J=8.6Hz, 1H), 7.14 (d, J=6.8 Hz, 2H), 6.95 (t, J=6.5 Hz, 1H), 6.92 (dd,J=8.8, 2.5 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.57 (t, J=7.4 Hz, 1H), 4.88(s, 2H), 4.66 (d, J=5.9 Hz, 2H), 3.57 (t, J=4.5 Hz, 4H), 3.33-3.31 (m,2H), 2.41-2.38 (m, 6H). m/z: 547.5 (MH⁺).

Example 76N-(2-Amino-phenyl)-4-{[6-(2-dimethylamino-ethoxy)-benzothiazol-2-ylamino]-methyl}-benzamide(138) Step 1:[2-(4-{[6-(2-Dimethylamino-ethoxy)-benzothiazol-2-ylamino]-methyl}-benzoylamino)-phenyl]-carbamicacid tert-butyl ester (133)

To a suspension of compound 129 (1.00 g, 2.04 mmol) in THF (6.8 mL) atroom temperature under N₂ atmosphere were successively addedN,N-dimethylethanolamine (225 μL, 2.24 mmol) and triphenylphosphine (696mg, 2.65 mmol) followed by diisopropyl azodicarboxylate (550 μL, 2.65mmol). Heat was evolved and the mixture turned dark red. It was stirredfor 4 h, THF was removed in vacuo and the dark residue was partitionedbetween EtOAc and H₂O. Organic phase was collected and extracted withHCl 1N. Acidic extract was separated and neutralized with saturatedaqueous NaHCO₃ under vigorous stirring. A white precipitate was formedwhich was collected by filtration to afford the title compound 133 (430mg, 37% yield). ¹H NMR: (acetone-d₆) δ(ppm): 7.99 (d, J=8.4 Hz, 2H),7.70 (dd, J=8.0, 2.2 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.56 (d, J=1.6 Hz,1H), 7.33 (d, J=9.0 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.19 (quint.d,J=7.8, 2.4 Hz, 2H), 6.87 (dd, J=8.8, 2.5 Hz, 1H), 4.80 (s, 2H), 4.08 (t,J=5.9 Hz, 2H), 2.67 (t, J=5.7 Hz, 2H), 2.27 (s, 6H), 1.48 (s, 9H). m/z:562.5 (MH⁺).

Step 2:N-(2-Amino-phenyl)-4-{[6-(2-dimethylamino-ethoxy)-benzothiazol-2-ylamino]-methyl}-benzamide(138)

The title compound 138 was obtained starting from the compound 133following the same procedures as for the Boc cleavage described inscheme 28, step 5 (example 68) (82% yield). ¹H NMR: (CD₃OD) δ(ppm): 7.96(d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.8 Hz, 1H), 7.23(d, J=2.5 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 7.07 (td, J=9.0, 1.6 Hz, 1H),6.90 (dd, J=8.8, 2.7 Hz, 1H), 6.89 (dd, J=6.5, 1.6 Hz, 1H), 6.76 (t,J=6.5 Hz, 1H), 4.71 (s, 2H), 4.10 (t, J=5.3 Hz, 2H), 2.79 (t, J=5.5 Hz,2H), 2.36 (s, 6H). m/z: 462.5 (MH⁺).

Example 77N-(2-Amino-phenyl)-4-{[6-(2-piperidin-1-yl-ethoxy)-benzothiazol-2-ylamino]-methyl}-benzamide(139)

The title compound 139 was obtained following the same procedures(two-step reaction sequence) described in example 76 but substitutingN,N-dimethylethanolamine for 1-piperidineethanol (52% yield over twosteps). ¹H NMR: (CD₃OD) δ(ppm): 7.96 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.2Hz, 2H), 7.36 (d, J=8.8 Hz, 1H), 7.32 (d, J=2.5 Hz, 1H), 7.17 (d, J=8.0Hz, 1H), 7.07 (td, J=6.1, 1.2 Hz, 1H), 6.97 (dd, J=8.8, 2.7 Hz, 1H),6.90 (d, J=7.8 Hz, 1H), 6.77 (t, J=7.2 Hz, 1H), 4.71 (s, 2H), 4.35 (t,J=4.9 Hz, 2H), 3.64-3.60 (m, 2H), 3.56 (t, J=4.9 Hz, 2H), 3.10-3.01 (m,2H), 2.05-1.92 (m, 2H), 1.90-1.81 (m, 4H). m/z: 502.5 (MH⁺).

Example 78N-(2-Amino-phenyl)-4-[(6-nitro-benzothiazol-2-ylamino)-methyl]-benzamide(142) Step 1:(2-{4-[(6-Nitro-benzothiazol-2-ylamino)-methyl]-benzoylamino}-phenyl)-carbamicacid tert-butyl ester (141)

The title compound 141 was obtained starting from compounds 140 and 128(described in the Patent Application WO 03/024448), following the sameprocedure as for the reductive amination described in scheme 3, step 2(example 12) (66% yield). ¹H NMR: (CD₃OD) δ(ppm): 9.78 (s, 1H), 9.28(bs, 1H), 8.71 (d, J=2.5 Hz, 1H), 8.64 (bs, 1H), 8.09 (dd, J=9.0, 2.5Hz, 1H), 7.92 (d, J=8.2 Hz, 2H), 7.51 (dd, J=8.6, 2.2 Hz, 2H), 7.46 (d,J=9.0, 2H), 7.17 (td, J=7.4, 1.8 Hz, 1H), 7.12 (td, J=7.1, 1.8 Hz, 1H),4.75 (bs, 2H), 1.42 (s, 9H). m/z: 542.2 (M+Na).

Step 2:N-(2-Amino-phenyl)-4-[(6-nitro-benzothiazol-2-ylamino)-methyl]-benzamide(142)

The title compound 142 was obtained following the same procedure as forthe Boc cleavage described in scheme 28, step 5 (example 68) usingcompound 141 as the starting material (98% yield). ¹H NMR: (DMSO-d₆):10.06 (s, 1H), 9.30 (bs, 1H), 8.71 (d, J=2.3 Hz, 1H), 8.09 (dd, J=9.0,2.3 Hz, 1H), 9.97 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 7.46 (d,J=8.8 Hz, 1H), 7.30 (d, J=7.0 Hz, 1H), 7.17 (t, J=7.8 Hz, 1H), 7.10 (d,J=7.8 Hz, 1H), 7.03 (t, J=7.2 Hz, 1H), 4.75 (d, J=5.5 Hz, 2H). m/z:420.5 (MH⁺).

Example 794-[(6-Amino-benzothiazol-2-ylamino)-methyl]-N-(2-amino-phenyl)-benzamide(144) Step 1:(2-{4-[(6-Amino-benzothiazol-2-ylamino)-methyl]-benzoylamino}-phenyl)-carbamicacid tert-butyl ester (143)

To a suspension of compound 141 (200 mg, 0.385 mmol) in a mixture ofTHF/MeOH/H₂O (10 mL/10 mL/10 mL) were successively added tin(II)chloride dihydrate (1.35 g, 8.46 mmol) and ammonium acetate (1.09 g,14.12 mmol). The mixture was refluxed for 2 days, the tin salts werefiltered off and the filtrate was concentrated in vacuo. The residue waspartitioned between EtOAc and H₂O (brine was added to break theemulsion). Organic phase was successively washed with saturated aqueousNaHCO₃ and brine, dried over MgSO₄, and concentrated in vacuo to affordthe title compound 143 (145 mg, 77% yield). ¹H NMR: (DMSO-d₆) δ (ppm):12.89 (bs, 1H), 10.79 (s, 1H), 8.12 (d, J=2.0 Hz, 1H), 8.05 (d, J=8.8Hz, 2H), 7.90-7.68 (m, 3H), 7.62 (d, J=8.4 Hz, 2H), 7.48 (bs, 1H), 7.21(dd, J=4.9, 3.7 Hz, 1H), 4.65 (s, 2H). m/z: 490.5 (MH⁺).

Step 2:4-[(6-Amino-benzothiazol-2-ylamino)-methyl]-N-(2-amino-phenyl)-benzamide(144)

The title compound 144 was obtained following the same procedures as forthe Boc-cleavage described in scheme 28, step 5 (example 68) usingcompound 143 as starting material. (58% yield). ¹H NMR: (DMSO-d₆): 9.58(s, 1H), 8.09 (t, J=5.9 Hz, 1H), 7.91 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.4Hz, 2H), 7.13 (d, J=7.0 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 6.94 (t, J=6.8Hz, 1H), 6.81 (d, J=2.2 Hz, 1H), 6.75 (dd, J=6.7, 1.2 Hz, 1H), 6.57 (t,J=6.5 Hz, 1H), 6.48 (dd, J=8.4, 2.2 Hz, 1H), 5.19 (s, 2H), 4.81 (s, 2H),4.58 (d, J=5.9 Hz, 2H). m/z: 390.5 (MH⁺)

Example 80N-(2-Amino-phenyl)-4-[(5,6-difluoro-benzothiazol-2-ylamino)-methyl]-benzamide(147) Step 1: 5,6-Difluoro-benzothiazol-2-ylamine (145)

The title compound 145 was obtained following the procedure described inJ. Het. Chem, 1971, 8 (309-310) starting from 4,5-difluoroaniline (95%yield). ¹H NMR: (DMSO-d₆) δ(ppm): 7.78 (dd, J=10.6, 8.6 Hz, 1H), 7.61(s, 2H), 7.32 (dd, J=11.9, 7.2 Hz, 1H). m/z: 337.5 (M+Na⁺)

Step 2: 4-[(5,6-Difluoro-benzothiazol-2-ylamino)-methyl]-benzoic acid(146)

The title compound 146 was obtained starting from the compound 145following the same procedure as for the reductive amination described inscheme 3, step 2 (example 12) (63% yield). ¹H NMR: (DMSO-d₆) δ (ppm):8.72 (t, J=5.9 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.82 (dd, J=10.4, 8.0Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.40 (dd, J=11.9, 7.4 Hz, 1H), 4.65 (d,J=5.7 Hz, 2H). m/z: 315.2 (MH⁺).

Step 3:N-(2-Amino-phenyl)-4-[(5,6-difluoro-benzothiazol-2-ylamino)-methyl]-benzamide(147)

The title compound 147 was obtained starting from the compound 146following the same procedure as for the BOP coupling reaction describedin scheme 1, step 5 (example 1) (32% yield). ¹H NMR: (DMSO-d₆): 9.59 (s,1H), 8.73 (t, J=5.9 Hz, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.83 (dd, J=10.4,8.0 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 7.40 (dd, J=11.9, 7.2 Hz, 1H), 7.13(d, J=7.8 Hz, 1H), 6.94 (td, J=7.8, 1.4 Hz, 1H), 6.75 (dd, J=7.8, 1.4Hz, 1H), 6.57 (td, J=7.6, 1.2 Hz, 1H), 4.87 (s, 2H), 4.65 (d, J=5.9 Hz,2H). m/z: 411.4 (MH⁺). Scheme 35

Compound X Compound Example X 153

157 81

154

158 82

155

159 83

156

160 84

Example 81N-(2-Amino-phenyl)-4-{6-[3-(2-morpholin-4-yl-ethyl)-ureido]-benzothiazol-2-ylsulfanylmethyl}-benzamide(157) Step 1:4-{6-[3-(2-Morpholin-4-yl-ethyl)-ureido]-benzothiazol-2-ylsulfanylmethyl}-benzoicacid methyl ester (149)

The title compound 149 was obtained following the same procedure as forthe carbamate formation described in scheme 32, step 1 (example 75), butsubstituting compound 129 for compound 148 (described in the PatentApplication WO 03/024448) (70% yield). ¹H NMR: (DMSO-d₆) δ (ppm): 9.28(bs, 1H), 8.18 (d, J=2.3 Hz, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.77 (d, J=8.6Hz, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.42 (dd, J=8.8, 2.2 Hz, 1H), 4.68 (s,2H), 3.82 (s, 3H), 3.59-3.58 (m, 4H), 3.33-3.32 (m, 2H), 3.21 (q, J=6.1Hz, 2H), 2.38-2.37 (m, 4H). m/z: 487.4 (MH⁺).

Step 2:4-{6-[3-(2-Morpholin-4-yl-ethyl)-ureido]-benzothiazol-2-ylsulfanylmethyl}-benzoicacid methyl ester (153)

The title compound 153 was obtained following the same procedure as forthe hydrolysis described in scheme 1, step 4 (example 1) using compound149 as starting material (50% yield). ¹H NMR: (DMSO-d₆) δ(ppm): 9.75(bs, 1H), 8.22 (d, J=2.2 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.8Hz, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.55 (d, J=6.3 Hz, 1H), 7.49 (dd,J=8.8, 2.2 Hz, 1H), 4.68 (s, 2H), 3.58 (t, J=4.3 Hz, 4H), 3.34-3.32 (m,2H), 3.21 (q, J=5.9 Hz, 2H), 2.38 (t, J=6.3 Hz, 4H). m/z: 473.4 (MH⁺).

Step 3:N-(2-Amino-phenyl)-4-{6-[3-(2-morpholin-4-yl-ethyl)-ureido]-benzothiazol-2-ylsulfanylmethyl}-benzamide(157)

The title compound 157 was obtained following the same procedures as theBOP coupling described in scheme 1, step 5 (example 1) using compound153 as starting material (26% yield). ¹H NMR: (DMSO-d₆) δ (ppm): 9.59(s, 1H), 8.84 (s, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.90 (d, J=8.2 Hz, 2H),7.71 (d, J=8.6 Hz, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.30 (dd, J=8.8, 2.2 Hz1H), 7.12 (d, J=7.0 Hz, 1H), 6.94 (t, J=7.0 Hz, 1H), 6.74 (dd, J=8.1,1.5 Hz, 1H), 6.56 (t, J=7.4 Hz, 1H), 6.14 (t, J=4.9 Hz, 1H), 4.88 (bs,2H), 4.66 (s, 2H) 3.58 (t, J=4.5 Hz, 4H), 3.31-3.30 (m, 2H), 3.21 (q,J=5.7 Hz, 2H), 2.38 (t, J=6.3 Hz, 4H). m/z: 563.5 (MH⁺).

Example 82N-(2-Amino-phenyl)-4-[6-(2-dimethylamino-acetylamino)-benzothiazol-2-ylsulfanylmethyl]-benzamide(158) Step 1:4-[6-(2-Dimethylamino-acetylamino)-benzothiazol-2-ylsulfanylmethyl]-benzoicacid methyl ester (150)

NaHCO₃ (356 mg, 4.24 mmol) was added to a suspension of compound 148(described in the Patent Application WO 03/024448) (701 mg, 2.12 mmol)and Me₂NCH₂COCl.HCl (670 mg, 4.24 mmol) in CH₃CN followed by addition ofEt₃N (295 μl, 2.12 mmol). The mixture was stirred at room temperature 24h, concentrated in vacuo and the residue was partitioned between DCM andH₂O. The aqueous layer was collected, neutralized with NaHCO₃ andextracted with fresh DCM, dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash chromatography on silica gel affordingthe title compound 150 (485 mg, 55% yield). ¹H NMR: (DMSO-d₆) δ(ppm):9.95 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.79 (d,J=8.8 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.63 (dd, J=8.8, 2.1 Hz, 1H),4.71 (s, 2H), 3.84 (s, 3H), 3.11 (s, 2H), 2.30 (s, 6H). m/z: 416.4(MH⁺).

Step 2:4-[6-(2-Dimethylamino-acetylamino)-benzothiazol-2-ylsulfanylmethyl]-benzoicacid (154)

The title compound 154 was obtained following same procedure as for thehydrolysis described in scheme 1, step 4 (example 1) using compound 150as starting material (78% yield). ¹H NMR: (DMSO-d₆) δ(ppm): 9.95 (s,1H), 8.41 (d, J=2.0 Hz, 1H), 7.86 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.8 Hz,1H), 7.63 (dd, J=9.0, 2.0 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 4.68 (s, 2H),3.11 (s, 2H), 2.30 (s, 6H). m/z: 402.4 (MH⁺).

Step 3:N-(2-Amino-phenyl)-4-[6-(2-dimethylamino-acetylamino)-benzothiazol-2-ylsulfanylmethyl]-benzamide(158)

Title compound 158 was obtained following the same procedures as the BOPcoupling described in scheme 1, step 5 (example 1) using compound 154 asstarting material (28% yield). ¹H NMR: (DMSO-d₆) δ (ppm): 9.93 (s, 1H),9.59 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 7.90 (d, J=8.0 Hz, 2H), 7.79 (d,J=9.0 Hz, 1H), 7.62 (dd, J=8.8, 2.2 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H),7.12 (d, J=7.6 Hz, 1H), 6.94 (t, J=8.0 Hz, 1H), 6.74 (dd, J=8.0, 1.6 Hz,1H), 6.56 (t, J=7.5 Hz, 1H), 4.88 (s, 2H), 4.69 (s, 2H), 3.09 (s, 2H),2.28 (s, 6H). HRMS: m/z: 491.1455±0.0014 (M⁺).

Example 83N-(2-Amino-phenyl)-4-[6-(dimethylamino-methyleneamino)-benzothiazol-2-ylsulfanylmethyl]-benzamide(159) Step 1:4-[6-(Dimethylamino-methyleneamino)-benzothiazol-2-ylsulfanylmethyl]-benzoicacid methyl ester (151)

To a pre-cooled (−78° C.) solution of trichloromethylchloroformate (74μL, 608 mmol) in THF (2 mL) under N₂ atmosphere was added via canula asolution of compound 148 (described in the Patent Application WO03/024448) (201 mg, 608 mmol) in a mixture of THF and DMF (3.5 mL, 0.5mL respectively) followed by addition of Et₃N (169 μL, 1.22 mmol). Thesolution was stirred at −78° C. for 1 h and at 0° C. for 2 h and allowedto warm to rt overnight. The solvents were removed in vacuo, and theresidue was partitioned between H₂O and a mixture of DCM/MeOH (9:1),dried over MgSO₄ and concentrated in vacuo, affording the title compound151 (136 mg, 58% yield). ¹H NMR: (DMSO-d₆) δ(ppm): 7.92 (d, J=8.4 Hz,2H), 7.81 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.46(d, J=2.2 Hz, 1H), 7.04 (dd, J=8.6, 2.2 Hz, 1H), 4.68 (s, 2H), 3.84 (s,3H), 3.04 (bs, 3H), 2.95 (bs, 3H). m/z: 386.4 (MH⁺).

Step 2:4-[6-(Dimethylamino-methyleneamino)-benzothiazol-2-ylsulfanylmethyl]-benzoicacid (155)

The title compound 155 was obtained following same procedure as for thehydrolysis described in scheme 1, step 4 (example 1) using compound 151as starting material (45% yield). ¹H NMR: (DMSO-d₆) δ (ppm): 7.89 (d,J=8.2 Hz, 2H), 7.80 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.59 (d, J=8.2 Hz,2H), 7.45 (d, J=2.2 Hz, 1H), 7.04 (dd, J=8.6, 2.2 Hz, 1H), 4.67 (s, 2H),3.03 (bs, 3H), 2.94 (bs, 3H). m/z: 372.3 (MH⁺).

Step 3:N-(2-Amino-phenyl)-4-[6-(dimethylamino-methyleneamino)-benzothiazol-2-ylsulfanylmethyl]-benzamide(159)

The title compound 159 was obtained following the same procedures as forthe BOP coupling described in scheme 1, step 5 (example 1) usingcompound 155 as starting material. (25% yield). ¹H NMR: (DMSO-d₆)δ(ppm): 9.60 (s, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.79 (s, 1H), 7.69 (d,J=8.6 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.44 (d, J=2.2 Hz, 1H), 7.13 (d,J=8.0 Hz, 1H), 7.03 (dd, J=8.6, 2.3 Hz, 1H), 6.95 (t, J=7.0 Hz, 1H),6.75 (d, J=9.2 Hz, 1H), 6.57 (t, J=7.4 Hz, 1H), 4.89 (s, 2H), 4.67 (s,2H), 3.02 (s, 3H), 2.93 (s, 3H). m/z: 462.5 (MH⁺).

Example 84N-(2-Amino-phenyl)-4-{6-[N-(2-Amino-phenyl)-4-benzylamide]-benzothiazol-2-ylsulfanylmethyl}-benzamide(160) Step 1: N-(4-methylbenzoic acid methylester)-benzothiazol-2-ylsulfanylmethyl}-benzoic acid methyl ester (152)

To a solution of compound 148 (9.52 g, 28.8 mmol) in DMF (30 mL) wasadded DCM (130 mL) and methyl-(4-bromomethyl)benzoate (6.60 g, 28.8mmol) was added and the mixture was stirred at rt for 16 h. The solventswere concentrated in vacuo and the resulting solid was partitionedbetween EtOAc and H₂O. The organic layer was washed with HCl 1N, brine,dried over MgSO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography using EtOAc/Hex (45:55) followed byBiotage pre-packed silica gel column using MeOH/DCM (2:98) andcrystallization in a mixture of CHCl₃ and Et₂O affording the titlecompound 152 (2.66 g, 19% yield). ¹H NMR: (DMSO-d₆) δ(ppm): 7.89 (d,J=8.0 Hz, 2H), 7.87 (d, J=7.8 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.54 (d,J=8.8 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 6.93 (d, J=2.3 Hz, 1H), 6.77 (dd,J=8.8, 2.5 Hz, 1H), 6.70 (t, J=6.1 Hz, 1H), 4.58 (s, 2H), 4.38 (d, J=6.3Hz, 2H), 3.81 (s, 3H), 3.81 (s, 3H). m/z: 479.4 (MH⁺).

Step 2: N-(4-methylbenzoicacid)-benzothiazol-2-ylsulfanylmethyl}-benzoic acid (156)

The title compound 156 was obtained following same procedure as for thehydrolysis described in scheme 1, step 4 (example 1) using compound 152as starting material and doubling the amount of lithium hydroxide (37%yield). m/z: 451.4 (MH⁺).

Step 3:N-(2-Amino-phenyl)-4-{6-[N-(2-Amino-phenyl)-4-benzamide]-benzothiazol-2-ylsulfanylmethyl}-benzamide(160)

The title compound 160 was obtained following the same procedures as forthe BOP coupling described in scheme 1, step 5 (example 1) usingcompound 156 as starting material and doubling the amount of allreagents (5% yield). ¹H NMR: (Acetone-d₆) d(ppm): 7.98 (d, J=8.0 Hz,2H), 7.96 (d, J=8.2 Hz, 2H), 7.63 (d, J=9.0 Hz, 1H), 7.62 (d, J=7.4 Hz,2H), 7.55 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.2 Hz, 2H), 7.04 (d, J=2.5 Hz,1H), 6.99 (t, J=7.4 Hz, 2H), 6.91 (dd, J=8.8, 2.3 Hz, 1H), 6.85 (d,J=7.4 Hz, 2H), 6.66 (t, J=7.4 Hz, 2H), 4.65 (s, 2H), 4.54 (s, 2H). m/z:631.5 (MH⁺). Scheme 36

Compounds Example L 163, 166 85 NH 164, 167 86

165, 168 87

Example 85N-(2-Amino-phenyl)-4-(6-methoxy-benzothiazol-2-ylamino)-benzamide (166)Step 1: 4-(6-Methoxy-benzothiazol-2-ylamino)-benzoic acid methyl ester(161)

To a solution of 2-chloro-6-methoxybenzothiazole (1.00 g, 5.03 mmol) inDMF (10 mL) was added methyl 4-aminobenzoate (760 mg, 5.03 mmol)followed by addition of powdered K₂CO₃ (1.81 g, 15.09 mmol). The mixturewas stirred at 90° C. for 16 h and at 120° C. for 24 h and then at 140°C. for 3 days. It was allowed to cool down to rt and NaH (60% in mineraloil, 201 mg, 5.03 mmol) was added. The mixture was stirred at rt for 16h and quenched with H₂O. The solvent was removed in vacuo at 80° C. andthe residue was partitioned between H₂O and EtOAc. The organic layer waswashed with HCl 1N, saturated NaHCO₃ and brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography using EtOAc/Hex and increasing polarity from 20:80 to50:50 throughout elution, affording the title compound 161 (150 mg, 9%yield). m/z: 315.2 (MH⁺)

Step 2: 4-(6-Methoxy-benzothiazol-2-ylamino)-benzoic acid (163)

The title compound 163 was obtained following same procedure as for thehydrolysis described in scheme 1, step 4 (example 1) using compound 161as starting material (66% yield). m/z: 301.2 (MH⁺).

Step 3:N-(2-Amino-phenyl)-4-(6-methoxy-benzothiazol-2-ylamino)-benzamide (166)

The title compound 166 was obtained following the same procedures as forthe BOP coupling described in scheme 1, step 5 (example 1) usingcompound 163 as starting material. (53% yield). ¹H NMR: (DMSO-d₆)δ(ppm): 10.62 (s, 1H), 9.53 (s, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.84 (d,J=9.2 Hz, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 6.59 (t,J=7.2 Hz, 1H), 4.89 (s, 2H), 3.78 (s, 3H). m/z: 391.4 (MH⁺).

Example 86N-(2-Amino-phenyl)-4-[3-(6-methoxy-benzothiazol-2-yl)-ureido]-benzamide(167) Step 1: 4-[3-(6-Methoxy-benzothiazol-2-yl)-ureido]-benzoic acidethyl ester (162)

The title compound 162 was obtained following the procedure described inJ. Med. Chem., 1979, 22 (1), 28-32, starting from2-amino-6-methoxybenzothiazole (93% yield). ¹H NMR: (DMSO-d₆) δ(ppm):9.63 (bs, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H), 7.55-7.51(m, 2H), 6.98 (d, J=8.8 Hz, 1H), 4.28 (q, J=6.8 Hz, 2H), 3.79 (s, 3H),1.32 (t, J=7.2 Hz, 3H). m/z: 372.3 (MH⁺).

Step 2: 4-[3-(6-Methoxy-benzothiazol-2-yl)-ureido]-benzoic acid (164)

The title compound 164 was obtained following same procedure as for thehydrolysis described in scheme 1, step 4 (example 1) using compound 162as starting material (99% yield). ¹H NMR: (DMSO-d₆) δ (ppm): 7.94 (d,J=8.4 Hz, 2H), 7.70 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.4 Hz, 1H), 7.49 (d,J=2.4 Hz, 1H), 6.96 (dd, J=8.8, 2.4 Hz, 1H), 3.80 (s, 3H). m/z: 344.3(MH⁺).

Step 3:N-(2-Amino-phenyl)-4-[3-(6-methoxy-benzothiazol-2-yl)-ureido]-benzamide(167)

The title compound 167 was obtained following the same procedures as theBOP coupling described in scheme 1, step 5 (example 1) using compound164 as starting material. (50% yield). ¹H NMR: (DMSO-d₆) δ(ppm): 9.58(s, H), 9.54 (bs, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.93 (s, 1H), 7.63 (d,J=8.8 Hz, 2H), 7.54 (d, J=9.2 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.14 (d,J=7.6 Hz, 1H), 6.98 (dd, J=8.0, 1.6 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H),6.77 (d, J=8.0 Hz, 1H), 6.59 (t, J=7.2 Hz, 1H), 4.89 (bs, 2H), 3.80 (s,3H). m/z: 434.4 (MH⁺).

Example 87N-(2-Amino-phenyl)-4-[3-(6-methoxy-benzothiazol-2-yl)-ureidomethyl]-benzamide(168) Step 1: 4-[3-(6-Methoxy-benzothiazol-2-yl)-ureidomethyl]-benzoicacid (165)

The title compound 165 was obtained following the same procedure as forthe carbamate formation described in scheme 32, step 1 (example 75)substituting compound 129 for 2-amino-6-methoxybenzothiazole and using4-aminomethylbenzoic acid instead of 4-(2-aminoethyl)-morpholine (28%yield). ¹H NMR: (DMSO-d₆) δ(ppm): 7.92 (t, J=8.0 Hz, 2H), 7.51 (d, J=8.5Hz, 1H), 7.47 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 6.95 (d, J=7.0 Hz, 1H),4.45 (s, 2H), 3.77 (s, 3H). m/z: 358.3 (MH⁺).

Step 2:N-(2-Amino-phenyl)-4-[3-(6-methoxy-benzothiazol-2-yl)-ureidomethyl]-benzamide(168)

The title compound 168 was obtained following the same procedures as theBOP coupling described in scheme 1, step 5 (example 1) using compound165 as starting material. (1.5% yield). ¹H NMR: (DMSO-d₆) δ(ppm): 10.75(bs, 14H), 9.63 (s, 1H), 7.97-7.91 (m, 2H), 7.53-7.43 (m, 3H), 7.33 (s,1H), 7.16 (s, 1H), 6.96-6.95 (m, 2H), 6.78 (d, J=8.0 Hz, 1H), 6.60-6.58(m, 1H), 4.88 (bs, 2H), 4.45 (s, 2H), 3.78 (s, 3H). Scheme 37

Compounds Ar 173, 175, 177

174, 176, 179

178

Example 88N-(2-Amino-phenyl)-4-{[5-(pyridin-2-ylsulfanyl)-thiazol-2-ylamino]-methyl}-benzamide(177) Step 1: 5-(Pyridin-2-ylsulfanyl)-thiazol-2-ylamine (169)

To a solution of 2-amino-5-bromothiazole hydrobromide (1.00 g, 3.85mmol) in DMF (8 mL) was added 2-mercaptopyridine (428 mg, 3.85 mmol)followed by addition of powdered K₂CO₃ (1.81 g, 15.09 mmol). The mixturewas stirred at 80° C. for 1 h and at rt for 16 h. The solvent wasremoved in vacuo at 80° C. and the compound was partitioned between H₂Oand EtOAc. The aqueous layer was extracted with EtOAc and the organicphase was extracted with HCl 1N. The acidic extract was neutralized withsaturated NaHCO₃ and the precipitate was extracted with EtOAc, washedwith brine, dried over MgSO₄ and concentrated in vacuo to afford thetitle compound 169 (589 mg, 73% yield). ¹H NMR: (Acetone-d₆) δ(ppm):8.36 (s, 1H), 7.66 (s, 1H), 7.20 (s, 1H), 7.12-7.05 (m, 2H), 6.84 (s,2H). m/z: 210.1 (MH⁺).

Step 2: 4-{[5-(Pyridin-2-ylsulfanyl)-thiazol-2-ylamino]-methyl}-benzoicacid methyl ester (173)

The title compound 173 was obtained starting from the compound 169following the same procedures as for the reductive amination describedin scheme 3, step 2 (example 12) (50% yield). ¹H NMR: (Acetone-d₆)δ(ppm): 8.37 (d, J=4.0 Hz, 1H), 7.99 (d, J=8.5 Hz, 2H), 7.83 (bs, 1H),7.67 (td, J=8.0, 1.5 Hz, 1H), 7.56 (d, J=7.5 Hz, 2H), 7.28 (s, 1H), 7.13(dd, J=6.5, 5.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 4.72 (bs, 2H), 3.88 (s,3H). m/z: 358.1 (MH⁺).

Step 3: 4-{[5-(Pyridin-2-ylsulfanyl)-thiazol-2-ylamino]-methyl}-benzoicacid (175)

The title compound 175 was obtained following the same procedures as forthe hydrolysis described in scheme 1, step 4 (example 1) using compound173 as starting material. (81% yield). ¹H NMR: (acetone-d₆) δ (ppm):8.37 (d, J=4.0 Hz, 1H), 7.99 (d, J=8.5 Hz, 2H), 7.83 (bs, 1H), 7.67 (td,J=8.0, 1.5 Hz, 1H), 7.56 (d, J=7.5 Hz, 2H), 7.28 (s, 1H), 7.13 (dd,J=6.5, 5.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 4.72 (bs, 2H), 3.88 (s, 3H).m/z: 344.0 (MH⁺).

Step 4:N-(2-Amino-phenyl)-4-{[5-(pyridin-2-ylsulfanyl)-thiazol-2-ylamino]-methyl}-benzamide(177)

The title compound 177 was obtained following the same procedures as forthe BOP coupling described in scheme 1, step 5 (example 1) usingcompound 175 as starting material. (53% yield). ¹H NMR: (DMSO-d₆)δ(ppm): 9.63 (s, 1H), 8.74 (t, J=5.9 Hz, 1H), 8.40 (d, J=3.7 Hz, 1H),7.96 (d, J=8.4 Hz, 2H), 7.72 (td, J=7.6, 2.0 Hz, 1H), 7.48 (d, J=7.8 Hz,2H), 7.34 (s, 1H), 7.19-7.15 (m, 2H), 7.05 (d, J=8.2 Hz, 1H), 6.97 (t,J=8.0 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 6.60 (t, J=7.8 Hz, 1H), 4.91 (s,2H), 4.59 (d, J=6.1 Hz, 2H). mz: 434.4 (MH⁺).

Example 89N-(2-Amino-phenyl)-4-{[5-(pyridin-2-yloxy)-thiazol-2-ylamino]-methyl}-benzamide(178) Step 1: 5-(Pyridin-3-yloxy)-thiazol-2-ylamine (170)

To a suspension of (NaH 60% in mineral oil, 169 mg, 4.23 mmol) in DME(10 mL) was added 2-hydroxypyridine (366 mg, 3.85 mmol). [Hydrogenevolution was observed]. Then, powdered K₂CO₃ (2.31 g, 19.2 mmol) wasadded followed by portion-wise addition of 2-amino-5-bromothiazolehydrobromide (1.00 g, 3.85 mmol). The mixture was refluxed with stirringfor 16 h and allowed to cool down to room temperature, quenched withwater and partitioned between water and EtOAc. The aqueous layer wasextracted with EtOAc and organic phase was extracted with HCl 1N. Theacidic extract was neutralized with saturated NaHCO₃ and the precipitatewas extracted first with EtOAc and then with a mixture of MeOH/CHCl₃(20:85). The combined organic extracts were dried over MgSO₄ andconcentrated in vacuo. The residue was crystallized by addition of amixture of MeOH/CHCl₃ (5:95) affording the title compound 170 (21 mg,3%). ¹H NMR: (CD₃OD) δ(ppm): 9.05 (dd, J=7.2, 2.0 Hz, 1H), 8.70 (ddd,J=9.2, 6.7, 2.2 Hz, 1H), 8.44 (s, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.59 (bs,2H), 7.58 (td, J=6.8, 1.4 Hz, 1H). m/z: 194.2 (MH⁺).

Step 2:[2-(4-{[5-(Pyridin-3-yloxy)-thiazol-2-ylamino]-methyl}-benzoylamino)-phenyl]-carbamicacid tert-butyl ester (173)

The title compound 173 was obtained following same procedure as for thereductive amination described in scheme 3, step 2 (example 12) reactingcompound 170 with compound 128 (described in the Patent Application WO03/024448) (46% yield). ¹H NMR: (acetone-d₆) δ (ppm): 9.66 (s, 1H), 8.30(s, 1H), 7.97 (d, J=8.2 Hz, 2H), 7.79 (ddd, J=7.0, 2.0, 0.6 Hz, 1H),7.68 (dd, J=7.6, 1.6 Hz, 1H), 7.60 (dd, J=7.8, 1.8 Hz, 1H), 7.55 (d,J=8.2 Hz, 2H), 7.45 (ddd, J=9.4, 6.7, 2.0 Hz, 1H), 7.27 (s, 1H), 7.21(td, J=7.4, 1.8 Hz, 1H), 7.16 (dt, J=7.4, 1.8 Hz, 1H), 6.50 (d, J=9.2Hz, 1H), 6.33 (td, J=6.7, 1.4 Hz, 1H), 4.67 (s, 2H), 1.99 (s, 9H). m/z:518.5 (MH⁺).

Step 3:N-(2-Amino-phenyl)-4-{[5-(pyridin-2-yloxy)-thiazol-2-ylamino]-methyl}-benzamide(178)

The title compound 178 was obtained following the same procedures as forthe Boc cleavage described in scheme 28, step 5 (example 68) usingcompound 171 as starting material. (82% yield). ¹H NMR: (acetone-d₆) δ(ppm): 8.00 (d, J=8.4 Hz, 2H), 7.82 (dd, J=6.3, 1.4 Hz, 1H), 7.56 (d,J=8.2 Hz, 2H), 7.46 (ddd, J=13.7, 6.7, 2.2 Hz, 1H), 7.30 (d, J=6.7 Hz,1H), 7.28 (s, 1H), 6.99 (td, J=13.7, 7.2 Hz, 1H), 6.87 (dd, J=6.7, 1.2Hz, 1H), 6.67 (t, J=7.2 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 6.34 (td,J=6.7, 5.3 Hz, 1H), 4.69 (s, 2H). m/z: 434.4 (MHz).

Example 90N-(2-Amino-phenyl)-4-[(4-pyridin-3-yl-thiazol-2-ylamino)-methyl]-benzamide(179) Step 1: 4-Pyridin-3-yl-thiazol-2-ylamine (172)

The title compound 172 was obtained following the procedure described inJ. Heterocycl. Chem., 1970, 7, (1137-1141). (94% yield). ¹H NMR: (CD₃OD)δ(ppm): 8.94 (dd, J=2.3, 0.8 Hz, 1H), 8.41 (dd, J=4.7, 1.6 Hz, 1H), 8.18(dt, J=8.6, 1.6 Hz, 1H), 7.43 (ddd, J=9.0, 3.9, 0.8 Hz, 1H), 7.03 (s,1H). m/z: 178.1 (MH⁺).

Step 2: 4-[(4-Pyridin-3-yl-thiazol-2-ylamino)-methyl]-benzoic acidmethyl ester (174)

The title compound 174 was obtained following the same procedures as forthe reductive amination described in scheme 3, step 2 (example 12) usingcompound 172 as starting material (33% yield). ¹H NMR: (Acetone-d₆)δ(ppm): 9.07 (dd, J=2.3, 0.8 Hz, 1H), 8.45 (dd, J=4.7, 1.6 Hz, 1H), 8.16(dt, J=8.6, 1.6 Hz, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H),7.52-7.49 (m, 1H), 7.34 (ddd, J=7.8, 4.7, 0.8, 1H), 7.14 (s, 1H), 4.76(s, 2H), 3.87 (s, 3H). m/z: 326.3 (MH⁺).

Step 3: 4-[(4-Pyridin-3-yl-thiazol-2-ylamino)-methyl]-benzoic acid (176)

The title compound 176 was obtained following the same procedure as forthe hydrolysis described in scheme 1, step 4 (example 1) using compound174 as starting material (27% yield). ¹H NMR: (DMSO-d₆) δ (ppm): 8.99(dd, J=2.0, 0.8, 1H), 8.42 (dd, J=4.7, 1.6 Hz, 1H), 8.23 (t, J=5.9 Hz,1H), 8.11 (dt, J=8.2, 2.0 Hz, 1H), 7.76 (d, J=8.2 Hz, 2H), 7.36 (ddd,J=7.8, 4.7, 0.8 Hz, 1H), 7.23 (d, J=8.2 Hz, 2H), 7.21 (s, 1H), 7.47 (d,J=5.5 Hz, 2H). m/z: 312.3 (MH⁺).

Step 4:N-(2-Amino-phenyl)-4-[(4-pyridin-3-yl-thiazol-2-ylamino)-methyl]-benzamide(179)

The title compound 179 was obtained following the same procedures as theBOP coupling described in scheme 1, step 5 (example 1) using compound176 as starting material (94% yield). ¹H NMR (CDCl₃) δ(ppm): 10.00 (s,1H), 9.00 (dd, J=3.1, 0.8 Hz, 1H), 8.43 (dd, J=4.7, 1.6 Hz, 1H), 8.33(t, J=6.3 Hz, 1H), 8.11 (dt, J=7.8, 2.3 Hz, 1H), 7.89 (d, J=8.6 Hz, 2H),7.62 (dd, J=5.9, 3.5 Hz, 1H), 7.50 (d, J=8.6 Hz, 2H), 7.37 (dd, J=7.8,4.7 Hz, 1H), 7.26 (dd, J=5.5, 3.5 Hz, 1H), 7.24 (s, 1H), 4.56 (d, J=5.9Hz, 2H). m/z: 402.1 (MH⁺). Scheme 38

Compounds Example X Y 181, 184, 188, 192 91 (CH₃)₂NCH₂CH₂O— F 182, 185,189, 193 92 CH₃O— CH₃O— 183, 186, 190, 194 93 F F 191, 195 94 Cl F

Example 91N-(2-Amino-phenyl)-4-[6-(2-dimethylamino-ethoxy)-5-fluoro-1H-benzoimidazol-2-ylsulfanylmethyl]-benzamide(192) Step 1: 5-(2-Dimethylamino-ethoxy)-4-fluoro-2-nitro-phenylamine(180)

A flame-dried round-bottomed flask was charged with4,5-difluoro-2-nitroaniline (2.00 g, 11.49 mmol) andN,N-dimethylethanolamine. Pyridine (44 mL) was added followed by slowaddition of NaH (60% in mineral oil, 965 mg, 24.1 mmol). The mixture wasput under N₂ atmosphere, stirred at rt for 16 h and quenched with H₂O.Solvents were removed in vacuo and the residue was partitioned betweenH₂O and EtOAc. The organic layer was extracted twice with HCl 1N, thecombined acidic extracts were neutralized with saturated NaHCO₃ to forma precipitate which was allowed to stand overnight, collected byfiltration and purified by flash chromatography using MeOH/CHCl₃ withincreasing polarity (10:90 to 15:85) to afford the title compound 180(1.30 g, 47% yield). ¹H NMR: (CD₃OD) δ (ppm): 7.76 (d, J=11.7 Hz, 1H),6.53 (d, J=7.4 Hz, 1H), 4.19 (t, J=5.5 Hz, 2H), 2.84 (t, J=5.5 Hz, 2H),2.37 (s, 6H). m/z: 244.2 (MH⁺).

Step 2: 4-(2-Dimethylamino-ethoxy)-5-fluoro-benzene-1,2-diamine (181)

A solution of intermediate 180 (220 mg, 0.904 mmol) in acetic acid (3.6mL) was degassed and put under N₂ atmosphere. A catalytic amount ofPd(OH)₂ was added and the black mixture was hydrogenated (1 atm) at rtfor 16 h, filtered through a celite pad and rinsed with MeOH. Thefiltrate was concentrated in vacuo at 80° C. to afford the titlecompound 181 as a mixture with AcONHEt₃ (252 mg, 75%). ¹H NMR: (CD₃OD) δ(ppm): 6.54 (d, J=7.8 Hz, 1H), 6.51 (d, J=12.3 Hz, 1H), 4.21 (t, J=5.1Hz, 2H), 3.40 (t, J=5.1 Hz, 2H), 2.89 (s, 6H). m/z: 214.1 (MH⁺).

Step 3: 6-(2-Dimethylamino-ethoxy)-5-fluoro-1H-benzoimidazole-2-thiol(184)

The title compound 184 was obtained following the procedure described inJ. Med. Chem., 1998, 63, 977-983, starting from the compound 181 (96%yield). ¹H NMR: (CD₃OD) δ(ppm): 7.16 (d, J=1.2 Hz, 0.5H), 7.07 (d,J=10.4 Hz, 1H), 7.04 (d, J=7.2 Hz, 0.5H), 4.37 (t, J=4.9 Hz, 2H), 3.50(t, J=5.1 Hz, 2H), 2.92 (s, 6H). m/z: 256.2 (MH⁺).

Step 4:4-[6-(2-Dimethylamino-ethoxy)-5-fluoro-1H-benzoimidazol-2-ylsulfanylmethyl]-benzoicacid (188)

The title compound 188 was obtained following same procedure as for thealkylation described in scheme 27, step 1 (examples 66 and 67) reactingcompound 184 with F-bromo-toluic acid (100% yield). ¹H NMR: (DMSO-d₆) δ(ppm): 12.65 (s, 1H), 7.92 (s, 1H), 7.83 (d, J=8.2 Hz, 2H), 7.51 (d,J=8.0 Hz, 2H), 7.30-7.27 (m, 1H), 4.58 (s, 2H), 4.40 (t, J=4.9 Hz, 2H),3.54 (t, J=4.9 Hz, 2H), 2.88 (s, 6H). m/z: 390.2 (MH⁺).

Step 5:N-(2-Amino-phenyl)-4-[6-(2-dimethylamino-ethoxy)-5-fluoro-1H-benzoimidazol-2-ylsulfanylmethyl]-benzamide(192)

The title compound 192 was obtained following the same procedure as forthe BOP coupling described in scheme 1, step 5 (example 1) usingcompound 188 as starting material. (30% yield). ¹H NMR: (acetone-d₆) δ(ppm): 9.02 (bs, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H),7.27 (d, J=7.6 Hz, 1H), 7.28-7.10 (m, 2H), 6.99 (td, J=8.0, 1.6 Hz, 1H),6.86 (dd, J=7.8, 1.2 Hz, 1H), 6.66 (t, J=8.8 Hz, 1H), 4.65 (s, 2H), 4.63(bs, 2H), 4.22 (bs, 2H), 2.87 (bs, 2H), 2.41 (s, 6H). m/z: 480.4 (MH⁺).

Example 92N-(2-Amino-phenyl)-4-(5,6-dimethoxy-1H-benzoimidazol-2-ylsulfanylmethyl)-benzamide(193) Step 1: 4,5-Dimethoxy-benzene-1,2-diamine (182)

A solution of 1,2-dimethoxy-4,5-dinitrobenzene (500 mg, 2.19 mmol) inMeOH (10 mL) was degassed and put under N₂ atmosphere. A catalyticamount of Pd on charcoal (10%) was quenched with MeOH (1 mL) andtransferred in one shot as a suspension in MeOH into the solution.Acetic acid (1.5 mL) was added and the black mixture was put under H₂atmosphere (1 atm), stirred at rt for 16 h. The mixture was filteredthrough a celite pad and rinsed with MeOH. The filtrate was concentratedin vacuo at 80° C. to afford the title compound 182 (residual aceticacid could not be removed from the product). ¹H NMR: (DMSO-d₆) δ(ppm):6.23 (s, 2H), 3.56 (s, 6H). m/z: 169.3. (MH⁺).

Step 2: 5,6-Dimethoxy-1H-benzoimidazole-2-thiol (185)

The title compound 185 was obtained following the procedure described inJ. Med. Chem., 1998, 63, 977-983, starting from compound 182. (44% yieldfor 2 steps). ¹H NMR: (DMSO-d₆) δ(ppm): 12.29 (s, 2H), 6.71 (s, 2H),3.74 (s, 6H). m/z: 211.2 (MH⁺).

Step 3: 4-(5,6-Dimethoxy-1H-benzoimidazol-2-ylsulfanylmethyl)-benzoicacid (189)

The title compound 189 was obtained following same procedure as for thealkylation described in scheme 27, step 1 (example 66 and 67) reactingcompound 185 with □-bromo-toluic acid (60% yield). ¹H NMR: (DMSO-d₆)δ(ppm): 7.83 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.06 (s, 2H),4.61 (s, 2H). m/z: 345.2 (MH⁺).

Step 4:N-(2-Amino-phenyl)-4-(5,6-dimethoxy-1H-benzoimidazol-2-ylsulfanylmethyl)-benzamide(193)

The title compound 193 was obtained following the same procedures as forthe BOP coupling described in scheme 1, step 5 (example 1) usingcompound 189 as starting material. (148 mg, 59% yield). ¹H NMR:(DMSO-d₆) δ(ppm): 12.30 (s, 1H), 9.55 (s, 1H), 7.85 (d, J=8.0 Hz, 2H),7.48 (d, J=8.4 Hz, 2H), 7.10 (d, J=7.8 Hz, 2H), 6.92 (td, J=7.2, 1.6 Hz,1H), 6.91-6.85 (bs, 1H), 6.73 (dd, J=8.2, 1.2 Hz, 1H), 6.55 (td, J=7.8,1.6 Hz, 1H), 4.85 (s, 2H), 4.52 (s, 2H), 3.74 (s, 6H). m/z: 435.5 (MH⁺).

Example 93N-(2-Amino-phenyl)-4-(5,6-difluoro-1H-benzoimidazol-2-ylsulfanylmethyl)-benzamide(194) Step 1: 4,5-Difluoro-benzene-1,2-diamine (183)

The title compound 183 was obtained following the same proceduredescribed as example 92, step 1 (scheme 38), but substituting1,2-dimethoxy-4,5-dinitrobenzene for 4,5-difluoro-2nitroaniline (97%yield). ¹H NMR: (CD₃OD) δ (ppm): 6.53 (t, J=10.0 Hz, 2H). m/z: 145.3(MH⁺).

Step 2: 5,6-Difluoro-1H-benzoimidazole-2-thiol (186)

The title compound 186 was obtained following the procedure described inJ. Med. Chem., 1998, 63, 977-983 starting from compound 183 (60% yield).¹H NMR: (CD₃OD) δ(ppm): 7.48 (s, 0.5H), 7.13 (d, J=8.4 Hz, 1H), 7.11 (d,J=6.4 Hz, 1H), 1.99 (s, 1.5H). m/z: 187.1 (MH⁺).

Step 3: 4-(5,6-Difluoro-1H-benzoimidazol-2-ylsulfanylmethyl)-benzoicacid (190)

The title compound 190 was obtained following same procedure as for thealkylation described in scheme 27, step 1 (example 66 and 67) reactingcompound 186 with □-bromo-toluic acid (59% yield). ¹H NMR: (DMSO-d₆)δ(ppm): 9.07 (s, 0.5H), 7.84 (d, J=8.0 Hz, 2H), 7.68 (s, 1.5H), 7.52 (d,J=8.2 Hz, 2H), 5.53-5.45 (m, 2H), 4.60 (s, 2H). m/z: 321.2 (MH⁺).

Step 4:N-(2-Amino-phenyl)-4-(5,6-difluoro-1H-benzoimidazol-2-ylsulfanylmethyl)-benzamide(194)

The title compound 194 was obtained following the same procedures as theBOP coupling described in scheme 1, step 5 (example 1) using compound186 as starting material (39% yield). ¹H NMR: (DMSO-d₆) δ (ppm): 9.59(s, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.55-7.40 (m,2H), 7.13 (d, J=7.6 Hz, 1H), 6.95 (t, J=7.6 Hz, 1H), 6.76 (d, J=7.4 Hz,1H), 6.58 (t, J=7.4 Hz, 1H), 4.61 (s, 2H). m/z: 411.4 (MH⁺).

Example 94N-(2-Amino-phenyl)-4-(5-chloro-6-fluoro-1H-benzoimidazol-2-ylsulfanylmethyl)-benzamide(195) Step 1:4-(6-Chloro-5-fluoro-1H-benzoimidazol-2-ylsulfanylmethyl)-benzoic acidmethyl ester (187)

The title compound 187 was obtained following same procedure as for thealkylation described in scheme 27, step 1 (example 66 and 67) reacting6-chloro-5-fluorobenzimidazole-2-thiol with methyl4-(bromomethyl)benzoate (54% yield). ¹H NMR: (DMSO-d₆) δ (ppm): (parent,missing protons: 7.85 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 3.80(s, 2H), 3.34 (s, 3H). m/z: 351.2 (MH⁺).

Step 2:4-(5-Chloro-6-fluoro-1H-benzoimidazol-2-ylsulfanylmethyl)-benzoic acid(191)

The title compound 191 was obtained following the same procedure as forthe hydrolysis described in scheme 1, step 4 (example 1) using compound187 as starting material (83% yield). ¹H NMR: (DMSO-d₆) δ (ppm): 7.88(d, J=8.2 Hz, 2H), 7.67 (d, J=6.8 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.53(d, J=6.8 Hz, 1H), 4.65 (s, 2H). m/z: 337.2 (MH⁺).

Step 3:N-(2-Amino-phenyl)-4-(5-chloro-6-fluoro-1H-benzoimidazol-2-ylsulfanylmethyl)-benzamide(195)

The title compound 195 was obtained following the same procedures as theBOP coupling described in scheme 1, step 5 (example 1) using compound191 as starting material (62% yield). ¹H NMR: (DMSO-d₆) δ (ppm): 12.87(bs, 1H), 9.56 (s, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.62-7.57 (m, 1H), 7.53(d, J=8.2 Hz, 2H), 7.52-7.48 (m, 1H), 7.10 (d, J=7.8 Hz, 1H), 6.92 (td,J=8.0, 1.6 Hz, 1H), 6.73 (dd, J=7.8, 1.4 Hz, 1H), 6.55 (t, J=7.4 Hz,1H), 4.86 (s, 2H), 4.61 (s, 2H). m/z: 427.4 (MH⁺).

Example 95N-(2-Hydroxy-phenyl)-4-(5-methoxy-1H-benzoimidazol-2-ylsulfanylmethyl)-benzamide(199) Step 1: 2-(tert-Butyl-dimethyl-silanyloxy)-phenylamine (196)

To a stirred solution of 2-aminophenol (3.00 g, 27.5 mmol) in DCM (150ml) was added tert-butyldimethylsilyl chloride (4.35 ml, 28.9 mmol) andEt₃N (4.02 ml, 28.9 mmol). The reaction mixture was stirred 16 h at roomtemperature. The organic phase was washed with water and brine, driedover anhydrous MgSO₄, filtered and concentrated. The residue waspurified by flash chromatography (5% AcOEt in hexane) to afford thetitle compound 196 (5.56 g, 91% yield). ¹H NMR (CDCl₃) δ (ppm): 7.61 (s,1H), 7.16 (s, 1H), 6.58 (s, 2H), 6.45 (s, 1H), 6.09 (s, 1H), 3.97 (s,3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.83 (s, 6H). m/z: 224.1 (MH⁺).

Step 2:N-[2-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-4-(5-methoxy-1H-benzoimidazol-2-ylsulfanylmethyl)-benzamide(198)

The title compound 198 was obtained following the same procedures as forthe BOP coupling described in scheme 1, step 5 (example 1) reacting thecompound 197 (described in the Patent Application WO 03/024448) with thecompound 196. m/z: 520.3 (MH⁺).

Step 3:N-(2-Hydroxy-phenyl)-4-(5-methoxy-1H-benzoimidazol-2-ylsulfanylmethyl)-benzamide(199)

To a stirred solution of compound 198 (313 mg, 0.600 mmol) in THF (15ml) was added TBAF 1M in THF (1.20 ml, 1.20 mmol). The reaction mixturewas stirred 16 h at room temperature. The solvent was evaporated and theresidue was dissolved in EtOAc, washed with sat. NH₄Cl and brine, driedover anhydrous MgSO₄, filtered and concentrated to afford the titlecompound 199 (150 mg, 61% yield) as a white powder. ¹H NMR (DMSO-d₆) δ(ppm): 9.72 (bs, 1H), 9.49 (bs, 1H), 7.90 (d, J=8.1 Hz, 2H), 7.63 (d,J=8.1 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.51 (d, J=9.5 Hz, 1H), 7.08-6.89(m, 4H), 6.81 (dd, J=7.0, 7.0 Hz, 1H), 4.76 (s, 2H), 3.81 (s, 3H). m/z:406.2 (MH⁺).

Example 96N-(2-Hydroxy-phenyl)-4-{[6-(2-morpholin-4-yl-ethoxy)-benzothiazol-2-ylamino]-methyl}-benzamide(201)

Title compound 201 was obtained following the same procedures describedin example 95 substituting compound 197 for compound 200 (described inthe Patent Application WO 03/024448) and using 1N HCl instead of TBAF inthe last step (26% yield). ¹H NMR: (CD₃OD) δ (ppm): 7.93 (d, J=8.5 Hz,2H), 7.79 (d, J=7.5 Hz, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.5 Hz,1H), 7.23 (s, 1H), 7.04 (t, J=7.0 Hz, 1H), 6.92-6.85 (m, 3H), 7.40 (s,2H), 4.14-4.12 (m, 2H), 3.72-3.70 (m, 4H), 2.81-2.79 (m, 2H), 2.62-2.60(m, 4H). m/z: 505.5 (MH⁺).

Example 97N-(2-Amino-phenyl)-4-[3-(pyridin-3-ylamino)-pyrrolidin-1-yl]-benzamide(206) Step 1: 4-(3-Hydroxy-pyrrolidin-1-yl)-benzoic acid tert-butylester (202)

The title compound 202 was obtained following the procedure described inJ. Heterocycl. Chem., 1994, 31, 1241, (91% yield). ¹H NMR: (CD₃OD)δ(ppm): 7.77 (d, J=9.0 Hz, 2H), 6.54 (d, J=9.0 Hz, 2H), 4.57-4.53 (m,1H), 3.57-3.50 (m, 2H), 3.45 (td, J=9.4, 3.3 Hz, 1H), 3.29 (dd, J=12.7,1.6 Hz, 1H), 2.22-2.13 (m, 1H), 2.10-2.03 (m, 1H), 1.59 (s, 9H). m/z:264.4 (MH⁺).

Step 2: 4-(3-Oxo-pyrrolidin-1-yl)-benzoic acid tert-butyl ester (203)

The title compound 203 was obtained following the procedure described inJ. Heterocycl. Chem., 1994, 31, 1241 (73% yield). ¹H NMR: (DMSO-d₆)δ(ppm): 7.74 (d, J=8.8 Hz, 2H), 6.67(d, J=9.0 Hz, 2H), 3.75 (s, 2H),3.69 (t, J=7.4 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H), 1.52 (s, 9H). m/z: 262.4(MH⁺).

Step 3: 4-[3-(Pyridin-3-ylamino)-pyrrolidin-1-yl]-benzoic acidtert-butyl ester (204)

The title compound 204 was obtained following the procedure as for thereductive amination described in scheme 3, step 2 (example 12) startingfrom compound 203 and using 3-aminopyridine instead of6-(pyridin-3-yl)pyridin-2-amine (11) (76% yield). ¹H NMR: (acetone-d₆) δ(ppm): 8.08 (d, J=2.7 Hz, 1H), 7.85 (dd, J=4.3, 1.6 Hz, 1H), 7.79 (d,J=9.0 Hz, 2H), 7.09 (ddd, J=8.2, 4.5, 0.8 Hz, 1H), 7.06 (ddd, J=8.2,2.7, 1.6 Hz, 1H), 6.58 (d, J=9.0 Hz, 2H), 4.33 (quint, J=4.9 Hz, 1H),3.79 (dd, J=10.2, 6.1 Hz, 1H), 3.60-3.54 (m, 1H), 3.51-3.45 (m, 1H),3.32 (dd, J=7.2, 4.1 Hz, 1H), 2.44 (sext., J=7.6 Hz, 1H), 2.18-2.11 (m,1H), 1.56 (s, 9H). m/z: 340.4 (MH⁺).

Step 4: 4-[3-(Pyridin-3-ylamino)-pyrrolidin-1-yl]-benzoic acid (205)

The title compound 205 was obtained following the same procedures as forthe Boc cleavage described in scheme 28, step 5 (example 68) usingcompound 204 as starting material (96% yield). ¹H NMR: (DMSO-d₆) d(ppm): 8.09 (d, J=2.0 Hz, 1H), 8.02(d, J=3.5 Hz, 1H), 7.74 (d, J=8.8 Hz,2H), 7.68-7.62 (m, 2H), 7.29-7.26 (m, 1H), 6.57 (d, J=8.8 Hz, 2H),4.29-4.26 (m, 1H), 3.71 (dd, J=10.6, 5.7 Hz, 1H), 3.51-3.42 (m, 2H),3.23 (dd, J=10.6, 3.5 Hz, 1H), 2.35 (sext., J=7.2 Hz, 1H), 2.06-1.98 (m,1H). m/z: 284.4 (MH⁺).

Step 5:N-(2-Amino-phenyl)-4-[3-(pyridin-3-ylamino)-pyrrolidin-1-yl]-benzamide(206)

The title compound 206 was obtained following the same procedures as forthe BOP coupling described in scheme 1, step 5 (example 1) usingcompound 205 as starting material (10% yield). ¹H NMR: (CD₃OD) δ(ppm):8.14 (s, 1H), 7.96 (d, J=2.3 Hz, 1H), 7.86 (d, J=9.0 Hz, 2H), 7.77 (dd,J=4.7, 1.4 Hz, 1H), 7.61-7.58 (m, 1H), 7.25 (dd, J=6.1, 3.1 Hz, 1H),7.18 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 7.15 (dd, J=8.0, 1.6 Hz, 1H), 7.11(ddd, J=8.2, 2.7, 1.4 Hz, 1H), 7.05 (td, J=7.2, 1.4 Hz, 1H), 6.89 (dd,J=8.0, 1.4 Hz, 1H), 6.76 (td, J=7.6, 1.4 Hz, 1H), 6.64 (d, J=8.8 Hz,2H), 4.26 (quint, J=4.3 Hz, 1H), 3.78 (dd, J=10.0, 6.1 Hz, 1H),3.62-3.56 (m, 1H), 3.53-3.47 (m, 1H), 3.31-3.29 (m, 1H), 2.42 (sext.,J=7.4 Hz, 1H), 2.12-2.08 (m, 1H). m/z: 374.4 (MH⁺).

Example 984-(2-Amino-benzothiazol-6-yloxymethyl)-N-(2-amino-phenyl)-benzamide(209) Step 1:{2-[4-(2-Amino-benzothiazol-6-yloxy)-benzoylamino]-phenyl}-carbamic acidtert-butyl ester (208)

The title compound 208 was obtained following the same procedure asapplied for the synthesis of compound 133 (scheme 32), using compound207 (described in the Patent Application WO 03/024448) instead ofdimethylamino-ethanol and substituting compound 129 (scheme 32) forcompound 127 (also mentioned in the scheme 32) (43% yield). ¹H NMR(DMSO-d₆) δ (ppm): 9.81 (s, 1H), 8.66 (s, 1H), 7.94 (d, J=8.4 Hz, 2H),7.58 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 7.37 (d, J=2.5 Hz 1H),7.23 (d, J=8.8 Hz, 1H), 7.18 (td, J=7.8, 1.8 Hz, 1H), 7.13 (td, J=7.6,1.6 Hz, 1H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 5.18 (s, 2H), 1.43 (s, 9H).m/z: 491.4 (MH⁺).

Step 2:N-(2-Amino-phenyl)-4-[3-(6-methoxy-benzothiazol-2-yl)-ureido]-benzamide(209)

The title compound 209 was obtained following the same procedures as theBoc cleavage described in scheme 28, step 5 (example 68) using compound208 as starting material. (28% yield). ¹H NMR: (DMSO-d₆) δ(ppm): 9.63(s, 1H), 7.96 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.37 (d, J=2.5Hz, 1H), 7.23 (s, 2H), 7.21 (d, J=8.8 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H),6.95 (td, J=8.8, 2.3 Hz, 1H), 6.89 (dd, J=8.6, 2.5 Hz, 1H), 6.75 (d,J=6.7 Hz, 1H), 6.57 (t, J=6.7 Hz, 1H), 5.16 (s, 2H), 4.89 (s, 2H). m/z:391.4 (MH⁺). Scheme 42

Cmpds 210-212 Ex Ar 212a  99

212b 100

212c 101

212d 102

212e 103

212f 104

212g 105

212h 106

212i 107

212j 108

212k 109

212l 110

212m 111

212n 112

212o 113

Example 99N-(2-Amino-phenyl)-4-[(4-methanesulfonyl-phenylamino)-methyl]-benzamide(212a) Step 1: 4-[(4-Methanesulfonyl-phenylamino)-methyl]-benzoic acid(211a)

Title compound was obtained by reacting 4-methanesulfonyl-phenylamine(210a) with 4-formyl-benzoic acid, following the procedure described inthe scheme 3, step 2 (example 12). ¹H NMR, (DMSO) δ (ppm): 7.87 (d,J=7.6 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.41 (d, J=7.6 Hz, 2H), 6.64 (d,J=8.0 Hz, 2H), 4.42 (s, 2H), 3.00 (s, 3H). LRMS: (calc.) 305.4; (obt.)304.3 (MH)⁺.

Step 2:N-(2-Amino-phenyl)-4-[(4-methanesulfonyl-phenylamino)-methyl]-benzamide(212a)

The compound was obtained by reacting the acid 211a with1,2-phenylenediamine following the procedure described in the scheme 1,step 5 (example 1). ¹H NMR: (DMSO) δ (ppm): 9.57 (bs, 1H), 7.90 (d,J=8.4 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.35 (t,J=6.0 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.93 (dt, J=1.6, 8.0 Hz, 1H),6.73 (dd, J=1.6, 8.0 Hz, 1H), 6.66 (d, J=8.8 Hz, 2H), 6.55 (dt, J=1.2,7.6 Hz, 1H), 4.88 (bs, 2H), 4.43 (d, J=6.0 Hz, 2H). LRMS: (calc.) 395.5;(obt.) 396.4 (MH)⁺.

Examples 100-113

Examples 100-113 (compounds 212b-o) were prepared using the sameprocedures as described for the compound 212a, example 99 (scheme 42,table 1) starting from the arylamines 210b-o via the intermediate acids211b-o (scheme 42). TABLE 6

Ex. Cmpd Ar Name Characterization Scheme 100 212b

N-(2-Amino- phenyl)-4-(pyridin- 3-ylaminomethyl)- benzamide ¹H NMR:(DMSO-d₆) δ(ppm): 9.60(bs, 1H), 7.98(d, J=2.7 Hz, 1H), 7.92(d, J'7.8 Hz,2H), 7.82(d, J=4.3 Hz, 1H), 7.46(d, J=8.2 Hz, 2H), 7.25(dd, J=5.1, 4.7Hz, 1H), 7.13(d, J=7.8 Hz, 2H), 6.85(dt, J=1.5, 7.4 Hz, 1H), 6.75(dd,J=1.6, 7.8 Hz, 1H), 6.58(ddd, J=7.8, 7.0 Hz, 1H), 4.43(s, 2H). 42 101212c

N-(2-Amino-Hz 1H), phenyl)-4-{[3-(2- methyl-pyrimidin-4-yl)-phenylamino]- methyl}-benzamide ¹H NMR: (CDCl₃) δ(ppm): 9.26(bs,1H), 8.34(dd, J=1.8, 5.3 Hz, 1H), 7.59(d, J=7.8 Hz, 2H), 7.37(d, J=4.9Hz, 1H), 7.17(d, J=8.2 Hz, 2H), 7.12(s, 1H), 6.96(d, J=8.0 Hz, 1H),6.85(t J=7.8 Hz, 1H), 6.80(d, J=7.2 Hz, 1H), 6.62(dd, J=6.0, 7.6 Hz,1H), # 6.43(d, J=8.0 Hz, 1H), 6.38-6.33(m, 1H), 6.25(dd, J=6.2, 7.6 Hz,1H), 4.10(s, 2H), 3.01(s, 3H). 42 102 212d

N-(2-Amino- phenyl)-4-[(6- chloro-pyridin-3- ylamino)-methyl]-benzainide ¹H NMR: (DMSO-d₆) δ(ppm): 9.43(bs, 1H), 7.77(d, J=8.0 Hz,2H), 7.56(d, J=1.8 Hz, 1H), 7.30(d, J=8.2 Hz, 2H), 6.99-6.96(m, 2H),6.84-6.78(m, 2H), 6.66(t, J=6.2 Hz, 1H), 6.61(d, 1H), 6.42(t, J=7.4 Hz,1H), 4.73(s, 2H), 4.24(d, J=6.3Hz, 2H). 42 103 212e

N-(2-Amino- phenyl)-4-[(3- hydroxy-4-methoxy- phenylamino)-methyl]-benzamide ¹H NMR: (DMSO-d₆) δ(ppm): 9.58(bs, 1H), 8.58(s, 1H),7.90(d, J=7.6 Hz, 2H), 7.43(d, J=8.0 Hz, 2H), 7.14(d J=7.6 Hz, 1H),6.95(dd, J=6.8, 8.4 Hz, 1H) 6.76(d, J=8.0 Hz, 1H) 6.62-6.52(m, 2H),6.09(d, J=2.4 Hz, 1H), 5.93-5.87(m, 2H), 4.88(s, 2H), 4.25(d, J=6.0 Hz,2H), 3.60(s, 3H). 42 104 212f

4-[(6-Acetylamino- pyridin-3-ylamino)- methyl]-N-(2- amino-phenyl)-benzamide ¹H NMR: (DMSO-d₆): 9.98(bs, 1H), 9.57(bs, 1H), 7.88(d, J=8.0Hz, 2H), 7.70(d, J=8.8 Hz, 1H), 7.62(d, J=2.8 Hz, 1H), 7.44(d, J=8.0 Hz,2H), 7.11(d, J=7.6 Hz, 1H), 6.95-6.90(m, 2H), 6.73(d, J=8.0 Hz, 1H),6.54(t, J=7.6 Hz, 1H), 6.36(t, J=6.0 Hz, 1H), # 4.87(s, 2H), 4.33(d,J=6.0 Hz, 2H), 1.97(s, 3H). 42 105 212g

N-(2-Amino- phenyl)-4-[(4- chloro-3- trifluoromethyl- phenylamino)-methyl]-benzamide ¹H NMR: (DMSO-d₆): 9.60(bs, 1H), 7.92(d, J=8.0 Hz,2H), 7.44(d, J=8.4 Hz, 2H), 7.30(d, J=8.4 Hz, 1H), 7.12(d, J=7.6 Hz,1H), 7.05-6.91(m, 2H), 6.79-6.74(m, 2H), 6.56(dd, J=6.8, 7.6 Hz, 1H),4.88(s, 2H), 4.40(d, J=6.0 Hz, 2H). 42 106 212h

N-(2-Amino- phenyl)-4-[(3- fluoro-4-methoxy- phenylamino)-methyl]-benzamide ¹H NMR: (DMSO-d₆): 9.56(bs, 1H), 7.89(d, J=8.0 Hz,2H), 7.43(d, J=8.0 Hz, 2H), 7.12(d, J=7.6 Hz, 1H), 6.93(dt, J=1.2, 8.0Hz, 1H), 6.85(t, J=8.8 Hz, 1H), 6.74(d, J=7.6 Hz, 1H), 6.56(t, J=7.6 Hz,1H), 6.40(dd, J=2.4, 14.0 Hz, 1H), 6.28(bd, J=10.0 Hz, # 1H), 6.23(t,J=6.4 Hz, 1H), 4.87(s, 2H), 4.28(s, 2H). 42 107 212i

N-(2-Amino- phenyl)-4-[(4- methanesulfonyl- phenylamino)-methyl]-benzamide ¹H NMR: (DMSO-d₆): 9.55(bs, 1H), 7.88(d, J=8.0 Hz,2H), 7.45-7.40(m, 4H), 7.12-7.07(m, 1H), 6.92(dd, J=1.6, 8.8 Hz, 1H),6.87(s, 2H), 6.73(dd, 1H), 6.59(d, J=8.8 Hz, 2H), 6.53(t, J=7.6 Hz, 1H),4.85(bs, 2H), 4.41(d, J=6.4 Hz, 2H). 42 108 212j

N-(2-Amino- phenyl)-4-[(3- chloro-4-fluoro- phenylamino)-methyl]-benzamide ¹H NMR: (DMSO-d₆): 9.58(bs, 1H), 7.90(d, J=8.0 Hz,2H), 7.41(d, J=8.4 Hz, 2H), 7.12(d, J=6.4 Hz, 1H), 7.08(t, J=9.2 Hz,1H), 6.94(dt, J=1.6, 8.0 Hz, 1H), 6.75(dd, J=1.6, 8.0 Hz, 1H),6.63-6.60(m, 1H), 6.58-6.48(m, 3H), 4.87(bs, 2H), 4.32(d, J=6.0 Hz, 2H).42 109 212k

N-(2-Amino- phenyl)-4-[(4- piperidin-1-yl- phenylamino)-methyl]-benzamide ¹H NMR: (DMSO-d₆): 9.56(bs, 1H), 7.88(d, J=8.0 Hz,2H), 7.43(d, J=8.0 Hz, 2H), 7.12(d, J=8.0 Hz, 1H), 6.94(t, J=7.3 Hz,1H), 6.74(d, J=8.0 Hz, 1H), 6.68(d, J=8.0 Hz, 2H), 6.56(t, J=8.0 Hz,1H), 6.45(d, J=8.8 Hz, 2H), 4.86(bs, 2H), 4.27(d, J=6.0 Hz, # 2H),2.84-2.82(m, 4H), 1.61-1.55(m, 4H), 1.46-1.43(m, 2H). 42 110 212l

N-(2-Amino- phenyl)-4-[(3- trifluoromethyl- phenylamino)-methyl]-benzainide ¹H NMR: (DMSO-d₆): 9.58(bs, 1H), 7.91(d, J=8.0 Hz,2H), 7.45(d, J=8.4 Hz, 2H), 7.22(dd, J=7.6, 8.4 Hz, 1H), 7.13(d, J=6.8Hz, 1H), 6.93(dt, J=1.6, 8.0 Hz, 1H), 6.86-6.83(m, 2H), 6.78(dd, J=2.0,8.0 Hz, 2H), 6.75(dd, J=1.6, 8.0 Hz, 1H), 6.56(dt, # J=1.6, 7.6 Hz, 1H),4.87(bs, 2H), 4.40(d, J=6.4 Hz, 2H). 42 111 212m

N-(2-Amino- phenyl)-4-[(5- cyano-pyridin-2- ylamino)-methyl]- benzamide¹H NMR: (DMSO-d₆): 9.57(bs, 1H), 8.36(d, J=2.0 Hz, 1H), 8.17(t, J=6.4Hz, 1H), 7.90(d, J=8.0 Hz, 2H), 7.68(dd, J=2.0, 8.8 Hz, 1H), 7.39(d,J=8.0 Hz, 2H), 7.13(d, J=8.0 Hz, 1H), 6.94(t, J=8.4 Hz, 1H), 6.75(dd,J=1.2, 7.6 Hz, 1H), 6.60-6.54(m, 2H), 4.87(bs, # 2H), 4.61 (d, J=5.6 Hz,2H). 42 112 212n

N-(2-Amino- phenyl)-4- (biphenyl-3- ylaminomethyl)- benzamide ¹H NMR:(Acetone-d₆) δ(ppm): 8.62(s, 1H), 8.40-8.37(m, 1H), 7.86(d, J=8.4 Hz,2H), 7.58(d, J=8.2 Hz, 2H), 7.54(dd, J=8.6, 1.4 Hz, 2H), 7.39(t, J=7.2Hz, 2H), 7.30(d, J=7.2 Hz, 1H), 7.17(t, J=7.6 Hz, 1H), 7.11(td, J=7.8,1.6 Hz, 1H), 7.06(td, # J=7.6, 1.6 Hz, 1H), 6.93(t, J=2.0 Hz, 1H),6.87(d, J=6.7 Hz, 1H), 6.76(dd, J=7.6, 1.6 Hz, 1H), 6.66(ddd, J=8.2,2.3, 1.0 Hz, 1H), 4.55(s, 2H). 42 113 212o

N-(2-Amino- phenyl)-4-[(4- phenoxy- phenylamino)- methyl]-benzamide ¹HNMR: (Acetone-d₆) δ(ppm): 9.06(bs, 1H), 7.99(d, J=8.2 Hz, 2H), 7.55(d,J=8.4 Hz, 2H), 7.28(dd, J=8.8, 7.2 Hz, 2H), 7.02-6.97(m, 1H), 6.86(dd,J=8.8, 1.0 Hz, 2H), 6.83(d, J=9.0 Hz, 2H), 6.70(d, J=8.6 Hz, 2H), 6.6(quint, J=7.4 Hz, 1H), # 4.65(bs, 2H), 4.47(s, 2H). 42

Example 114 N-(2-Amino-phenyl)-4-hydroxymethyl-benzamide (213)

In a flask containing 4-formylbenzoic acid (300 mg, 1.8 mmol) was addeddibutyltin dichloride (55 mg, 0.18 mmol), followed by THF (5 ml) andphenylsilane (0.187 ml, 1.8 mmol). The resulting mixture was stirredovernight at room temperature under nitrogen, concentrated and used forthe next step (coupling with o-phenylene-diamine) without furtherpurification, following the procedures described in the scheme 1, step 5(example 1), to afford the compound 213 (378 mg, 78% yield). ¹H NMR:(DMSO) δ (ppm): 9.63 (s, 1H), 7.94 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.5 Hz,2H), 7.16 (d, J=7.5 Hz, 1H), 6.96 (t, J=7.0 Hz, 1H), 6.78 (d, J=6.5,1H), 6.59 (dd, J=7.0, 7.5 Hz, 1H), 4.88 (s, 1H), 4.57 (s, 2H). LRMS:(calc.) 242.3; (obt.) 243.4 (MH)⁺. Scheme 44

Compound Example X Y Z R 218a 115 F F CH

218b 116 F H CH

218c 117 Br H N

Example 115N-(2-Amino-phenyl)-4-[(3-fluoro-4-morpholin-4-yl-phenylamino)-methyl]-benzamide(218a) Step 1: 4-(2-Fluoro-4-nitro-phenyl)-morpholine (215a)

To a solution of 214a (3 g, 18.85 mmol) in DMF (20 mL) were addedmorpholine (1.6 ml, 18.85 mmol) and K₂CO₃ (10.4 g, 75.4 mmol) at roomtemperature. The reaction mixture was heated at 60° C. for 16 h, cooled,filtered and concentrated in vacuo. The residue was purified by flashchromatography on silica gel, eluent with AcOEt/hexane (40:60) to affordtitle compound 215a as a white solid (4.0 g, 89% yield). LRMS: 226.2(calc.); 227.3 (obt.) (MH)⁺.

Step 2: 3-Fluoro-4-morpholin-4-yl-phenylamine (216a)

Title compound 216a was obtained by catalytic hydrogenation of nitrocompound 215a, following the procedure described in the scheme 38, step1 (example 92) (92% yield). LRMS: 196.2 (calc.); 197.2 (obt.) (MH)⁺.

Step 3: 4-[(3-Fluoro-4-morpholin-4-yl-phenylamino)-methyl]-benzoic acid(217a)

Title compound 226a was obtained via a reaction of 4-formylbenzoate withamine 216a, following the procedure described in the scheme 3, step 2(example 12) (91% yield). LRMS: 330.4 (calc.); 331.5 (obt.) (MH)⁺.

Step 4:N-(2-Amino-phenyl)-4-[(3-fluoro-4-morpholin-4-yl-phenylamino)-methyl]-benzamide(218a)

Title compound 218a was obtained reacting acid 217a with1,2-phenylenediamine following the procedures described in the scheme 1,step 5 (example 1) (40% yield). ¹H NMR: (DMSO) δ (ppm): 9.57 (s, 1H),7.91 (d, J=7.9 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H), 7.14 (d, J=7.5 Hz, 1H),6.95 (t, J=7.5; 7.0 Hz, 1H), 6.82-6.74 (m, 2H), 6.57 (dd, J=7.0; 7.5 Hz,1H), 6.37-6.30 (m, 2H), 4.86 (bs, 2H), 4.30 (d, J=5.71 Hz, 2H), 3.66(bs, 4H), 2.80 (bs, 4H). LRMS: (calc.) 420.2; (obt.) 421.2 (MH)⁺.

Examples 116-117 (Compounds 218b-c)

Examples 116-117 (compounds 218b-c) were prepared using the sameprocedures as described for the compound 218a (example 116, scheme 44)(table 3). TABLE 7

Ex Cmpd R Y Z Name Characterization Scheme 117 218b

H CH N-(2-Amino- phenyl)-4-{[4- (2-morpholin- 4-yl-ethoxy)-phenylamino]- methyl}- benzamide ¹H NMR: (DMSO-d₆) δ(ppm): 9.64(bs, 1H),7.97(d, J=8.4 Hz, 2H), 7.52(d, J=7.9 Hz, 2H), 7.20 (d, J=7.5 Hz, 1H),7.02(dd, J=7.0, 7.5 Hz, 1H), 6.83(d, J=7.91, 1H), 6.77(d, J=8.8 Hz, 2H),6.65(t, J=7.5 Hz, # 1H), 6.57(d, J=8.8 Hz, 2H), 4.36(bs, 2H), 4.07(bs,2H), 3.72(bs, 4H), 3.00(bs, 2H),2.82(bs, 4H). 44 118 218c

H N N-(2-Amino- phenyl)-4-[(6- morpholin-4- yl-pyridin-3- ylamino)-methyl]- benzamide ¹H NMR: (CDCl₃) δ(ppm): 9.59(bs, 1H), 7.91(d, J=8.3Hz, 2H), 7.57(d, J=2.9 Hz, 1H), 7.46(d, J=8.3 Hz, 2H), 7.14(d, J=8.3 Hz,1H), 7.97-6.93(m, 2H), 6.76(d, J=7.8 Hz, 1H), 6.64(d, J=8.8 Hz, 1H),6.58(t, J=7.8 Hz, 1H), # 4.88(bs, 2H), 4.30(d, J=5.8 Hz, 2H),3.66-3.64(m, 4H), 3.16-3.14(m, 4H). 44

Example 118N-(2-Amino-phenyl)-4-{[4-methoxy-3-(2-morpholin-4-yl-ethoxy)-phenylamino]-methyl}-benzamide(222) Step 1: 4-Methoxy-3-(2-morpholin-4-yl-ethoxy)-phenylamine (220)

To a solution of 4-(2-chloro-ethyl)-morpholine (2.67 g, 14.4 mmol) in asolvent mixture pyridine (5 mL) and DMF (15 ml) were added amine 219(2.00, 14.4 mmol) and K₂CO₃ (7.96 g, 57.6 mmol) at room temperature. Thereaction mixture was heated at 60° C. overnight, cooled, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel eluting with 70:30 AcOEt/hexane to afford title compound229 (3.6 g, 100% yield). LRMS: 252.3 (calc.); 253.3 (obt.) (MH)⁺.

Step 2:4-{[4-Methoxy-3-(2-morpholin-4-yl-ethoxy)-phenylamino]-methyl}-benzoicacid (221)

Title compound 221 was obtained reacting 4-formylbenzoate with amine220, following the procedure described in the scheme 3, step 2 (example12) (1.9 g, 99% yield). LRMS: 386.4 (calc.); 387.4 (obt.) (MH)⁺.

Step 3:N-(2-Amino-phenyl)-4-{[4-methoxy-3-(2-morpholin-4-yl-ethoxy)-phenylamino]-methyl}-benzamide(222)

Title compound 222 was obtained by coupling of the acid 221 (5.07 mmol)with 1,2-phenylenediamine (5.07 mmol) following the procedure describedin the scheme 1, step 5 (example 1) (260 mg, 11% yield). ¹H NMR: (DMSO)δ (ppm): 9.59 (s, 1H), 7.92 (d, J=7.5 Hz, 2H), 7.45 (d, J=7.9 Hz, 2H),7.15 (d, J=7.9 Hz, 1H), 6.96 (dd, J=8.5; 6.5 Hz, 1H), 6.77 (d, J=8.5 Hz,1H), 6.65 (d, J=8.5 Hz, 1H), 6.58 (t, J=7.5 Hz, 1H), 6.31 (d, J=2.5 Hz,1H), 6.03 (d, J=8.5 Hz, 1H), 4.86 (bs, 2H), 4.30 (d, J=5.5 Hz, 2H), 3.95(dd, J=5.9, 5.5 Hz, 2H), 3.59 (s, 3H), 3.56 (bs, 4H), 2.63 (bs, 2H),2.44 (bs, 4H). LRMS: 476.6 (calc.); 477.6 (obt.) (MH)⁺.

Example 119N-(2-Amino-phenyl)-4-(3,4-dimethoxy-phenylsulfamoyl)-benzamide (224)Step 1: N-(3,4-Dimethoxy-phenyl)-4-iodo-benzenesulfonamide (223)

The title compound 223 was obtained following the procedure described inthe Patent application No WO 01/38322 A1, by reacting3,4-dimethoxy-phenylamine with 4-iodo-benzenesulfonyl chloride (80%yield). LRMS: 419.2 (calc.); 420.2 (obt.) (MH)⁺.

Step 2: N-(2-Amino-phenyl)-4-(3,4-dimethoxy-phenylsulfamoyl)-benzamide(224)

A mixture of 223 (705 mg, 1.7 mmol), 1,2-phenylenediamine (199 mg, 1.84mmol), Pd(OAc)₂ (0.25 mmol, 15%) and 1,1′-bis(diphenylphosphino)ferrocene (160 mg, 0.29 mmol) was suspended in degassed DMF (10 mL),treated with Et₃N (700 μL, 5.04 mmol), heated under CO atmosphere(balloon) for 18 h at 70° C. After evaporation of the DMF in vacuo, theresidue was purified by flash chromatography (eluent AcOEt:hexane, 3:1)to give the title compound 224 (100 mg, 14% yield). ¹H-NMR (CD₃OD-d4), δ(ppm): 10.05 (s, 1H), 9.76 (s, 1H), 8.06 (d, J=8.3 Hz, 2H), 7.79 (d,J=7.8 Hz, 2H), 7.11 (bs, 1H), 6.94 (bs, 1H), 6.77-6.69 (m, 3H), 6.54(bs, 2H), 4.91 (bs, 2H), 3.62 (s, 3H). Scheme 47

Compounds 225-228 Example R Ar a 120 H

b 121 H

c 122 Me

d 123 Me

e 124 H

f 125 H

Example 120N-(2-Amino-phenyl)-4-[4-(4-methoxy-phenyl)-pyrimidin-2-ylsulfanylmethyl]-benzamide(228a) Step 1:4-[4-(4-Methoxy-phenyl)-pyrimidin-2-ylsulfanylmethyl]-benzoic acidmethyl ester (226a)

To a solution of 4-(4-methoxy-phenyl)-pyrimidine-2-thiol (225a) (1.00 g,4.58 mmol) in DMF (30 mL) was added 4-bromomethyl-benzoic acid methylester (1.05 g, 4.58 mmol). The mixture was heated at 60° C. for 1 h andevaporated to dryness to form the compound 226a, which was used in thenext without purification. LRMS=366.4 (calc.), 367.4 (found).

Step 2: 4-[4-(4-Methoxy-phenyl)-pyrimidin-2-ylsulfanylmethyl]-benzoicacid (227a)

To a stirred solution of 226a (4.58 mmol) in THF (20 ml) and MeOH (20ml) at room temperature was added a solution of LiOH—H₂O (960 mg, 22.9mmol) in water (50 ml). The reaction mixture was stirred 18 h at roomtemperature, diluted in water and acidified with 1N HCl (pH 5-6) to forma precipitate which was collected by filtration, washed with water anddried to afford the title compound 227a (1.64 g, 99% yield). LRMS(calc.): 352.4, (found): 353.4.

Step 3:N-(2-Amino-phenyl)-4-[4-(4-methoxy-phenyl)-pyrimidin-2-ylsulfanylmethyl]-benzamide(228a)

The title compound 228a was obtained by coupling of acid 227a with1,2-phenylenediamine following the procedures described in the scheme 1,step 5 (example 1) (80% yield). ¹H NMR: (DMSO) δ (ppm): 9.57 (bs, 1H),8.59 (d, J=5.5 Hz, 2H), 8.16 (d, J=7.0 Hz, 2H), 7.88 (d, J=8.2 Hz, 2H),7.70 (d, J=5.0 Hz, 1H), 7.57 (d, J=8.2, 2H), 7.12-7.07 (m, 2H), 6.93(dd, J=8.2, 7.0 Hz, 1H), 6.73 (dd, J=8.2, 1.6 Hz, 1H), 6.55 (dt, J=8.6,1.1 Hz, 1H), 4.86 (bs, 2H), 4.55 (s, 2H), 3.83 (s, 3H) LRMS: (calc.)442.5; (obt.) 443.5 (MH)⁺.

Examples 121-125

Examples 121-125 (compounds 228b-f) were prepared using the sameprocedures as described for the compound 228a, example 121 (scheme 47,table 1) starting from the thiophenols 225b-f via the intermediates226b-f and 227b-f (scheme 47). TABLE 8

Ex Cmpd Ar R Name Characterization Scheme 121 228b

H N-(2-Amino- phenyl)-4-(4- thiophen-2-yl- pyrimidin-2- ylsulfanylmethyl)-benzamide ¹H NMR: (DMSO-d₆) δ(ppm): 9.57 (bs, 1H), 8.59 (d, J=5.1 Hz,1H), 8.07 (dd, J=1.2, 3.9 Hz, 1H), 7.87-7.82 (m, 3H), 7.68 (d, J=5.1 Hz,1H), 7.59 (d, J=8.2, 2H), 7.24 (dd, J=5.1, 3.5 Hz, 1H), 7.10 (d, J=7.0Hz, 1H), 6.93 (dt, J=7.8, 1.6 Hz, # 1H), 6.73 (dd, J=7.8, 1.2 Hz, 1H),6.55 (dt, J=7.4, 1.2 Hz, 1H), 4.87 (bs, 2H), 4.51 (s, 2H). 47 122 228c

Me N-(2-Amino- phenyl)-4-(4- pyridin-3-yl- pyrimidin-2- ylsulfanylmethyl)-benzaimide ¹H NMR: (DMSO-d₆) δ(ppm): 9.65 (bs, 1H), 9.45-9.21 (m,1H), 8.66-8.60 (m, 2H), 8.41-8.39 (m, 1H), 7.77-7.76 (m, 3H), 7.52- 7.41(m, 3H), 7.05-6.98 (m, 1H), 6.81 (dd, J=6.8, 7.2 Hz, 1H), 6.61 (d, J=6.9Hz, 1H), 6.42 (dd, J=7.0, 8.8 Hz, 1H), 4.74 (bs, 2H), 4.46 (s, 2H). 47123 228d

Me N-(2-Amino- phenyl)-4-{1- [4-(4-methoxy- phenyl)- pyrimidin-2-ylsulfanyl]- ethyl}- benzamide ¹H NMR: (CDCl₃) δ(ppm): 9.58 (bs, 1H),8.57 (d, J=5.3 Hz, 1H), 8.13 (dd, J=2.1, 6.8 Hz, 2H), 7.91 (d, J=8.0 Hz,2H), 7.68 (d, J=5.5 Hz, 1H), 7.63 (d, J=8.2, 2H), 7.12 (m, 3H), 6.93(dt, J=1.4, 7.8 Hz, 1H), 7.40 (dd, J= # 1.4, 8.0 Hz, 1H), 6.56 (dt,J=1.3, 7.6 Hz, 1H), 4.87 (s, 2H), 3.83 (s, 3H), 1.76 (d, J=7.0 Hz, 3H).47 124 228e

H N-(2-Amino- phenyl)-4-(5- pyridin-2-yl- 4,5-dihydro- [1,3,4]thiadiazol-2- ylsulfanylmethy l)-benzamide ¹H NMR: (CD₃OD) δ(ppm): 9.60 (bs, 1H),8.58 (bd, J=4.7 Hz, 1H), 8.24 (s, 1H), 7.90 (d, J=8.1 Hz, 2H), 7.87-7.80(m, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.43-7.39 (m, 1H), 7.11 (d, J=7.2 Hz,1H), 6.93 (dt, J=1.6, 8.0 Hz, 1H), 6.74 # (dd, J=1.4, 8.0 Hz, 1H), 6.55(ddd, J=1.6, 6.3, 7.4 Hz, 1H), 4.88 (bs, 2H), 4.56 (s, 2H). 47 125 228f

H N-(2-Amino- phenyl)-4-[6-(4- chloro-phenyl)- pyridin-2-ylsulfanylmethy l]-benzaimide ¹H NMR: (CD₃OD) δ(ppm): 9.57 (bs, 1H),8.68 (d, J=5.2 Hz, 1H), 8.20 (bd, J=8.8 Hz, 2H), 7.88 (d, J=8.2 Hz, 2H),7.80 (d, J=5.2 Hz, 1H), 7.62-7.55 (m, 4H), 7.10 (d, J=7.6 Hz, 1H), 6.92(dt, J=1.6, 8.0 Hz, 1H), 6.72 (dd, J=1.4, 8.0 Hz, # 1H), 6.54 (dt,J=1.2, 7.6 Hz, 1H), 4.86 (bs, 2H), 4.55 (s, 2H). 47

Example 1264-[4-(2-Amino-phenylcarbamoyl)-benzylamino]-2-methylsulfanyl-pyrimidine-5-carboxylicacid amide (232a) Step 1:4-[(5-Cyano-2-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-benzoic acidmethyl ester (230a)

To a solution of 4-amino-2-methylsulfanyl-pyrimidine-5-carbonitrile(229a) (200 mg, 1.2 mmol) in DME (10 ml) were added4-bromomethyl-benzoic acid methyl ester (274 mg, 1.2 mmol) and K₂CO₃(663 mg, 4.8 mmol) at room temperature. The reaction mixture was heatedat 100° C. for 5 h, overnight at 60° C., cooled, filtered andconcentrated in vacuo. The crude product was used in the next reactionwithout further purification. LRMS: 314.3 (calc.); 315.3 (obt.) (MH)⁺.

Step 2:4-[(5-Carbamoyl-2-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-benzoicacid (231a)

Title compound 231a was obtained following the procedure described inexample 121, step 2 (scheme 47) but substituting compound 226a forcompound 230a (227 mg, 60% yield). LRMS (calc.): 318.3, (found): 319.3.

Step 3:4-[4-(2-Amino-phenylcarbamoyl)-benzylamino]-2-methylsulfanyl-pyrimidine-5-carboxylicacid amide (232a)

Title compound 232a was obtained by a coupling reaction of acid 231awith 1,2-phenylenediamine following the procedure described in thescheme 1, step 5 (example 1) (80% yield). ¹H NMR: (DMSO) δ (ppm): 9.39(bs, 1H), 9.35 (bs, 2H), 8.32 (s, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.22 (d,J=8.2 Hz, 2H), 6.94 (d, J=7.6 Hz, 1H), 6.75 (dt, J=1.4, 8.2, 1H), 6.56(dd, J=1.5, 8.0 Hz, 1H), 6.39 (t, J=7.4 Hz, 1H), 4.54 (s, 2H), 2.30 (s,3H). LRMS: (calc.) 408.5; (obt.) 409.5 (MH)⁺.

Example 1274-[4-(2-Amino-phenylcarbamoyl)-benzylamino]-2-pyridin-3-yl-pyrimidine-5-carboxylicacid amide (232b)

Title compound 232b was prepared following the same procedures asdescribed for the compound 232a, example 126 (scheme 48) starting fromthe aminonitrile 229b via the intermediates 230b and 231b. ¹H NMR:(DMSO-d₆) δ(ppm): 9.48 (bs, 3H), 8.86 (s, 1H), 8.74-8.73 (m, 1H),8.64-8.61 (m, 1H), 8.19 (bs, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.71 (bs, 1H),7.60-7.57 (m, 3H), 7.18 (d, J=8.4 Hz, 1H), 7.00 (t, J=6.8 Hz, 1H), 6.81(d, J=8.8 Hz, 1H), 6.63 (t, J=8.0 Hz, 1H), 4.95 (d, J=6.8 Hz, 2H).

Example 128N-(2-aminophenyl)-4-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)benzamide(237) Step 1:4-[4-(4-Trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acidtert-butyl ester (235)

To a solution of 1-(4-trifluoromethyl-pyridin-2-yl)-piperazine (233)(500 mg, 2.16 mmol) in DMSO were added 4-fluoro-benzoic acid tert-butylester (466 mg, 2.37 mmol) (234) and K₂CO₃ (1.2 g, 11.3 mmol). Themixture was heated for 16 h at 130° C., cooled, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(eluent AcOEt-hexane from 40:60 to pure AcOEt) to afford the titlecompound 244 (162 mg, 18% yield). LRMS: (calcd.) 406.4: (found) 407.4(MH)⁺.

Step 2: 4-[4-(4-Trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-benzoicacid (236)

The title compound 236 was obtained starting from the compound 235following the procedure described in the scheme 28, step 5 (example 68)(99% yield). LRMS 350.3 (calcd.), 351.3 (found).

Step 3:N-(2-Amino-phenyl)-4-[4-(4-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-benzamide(237)

The title compound 237 was obtained by coupling acid 236 with1,2-phenylenediamine following the procedure described in the scheme 1,step 5 (example 1) (96% yield). ¹H NMR: (DMSO) δ (ppm): 9.43 (bs, 1H),8.43 (s, 1H), 7.93 (bs, 2H), 7.88 (d, J=8.8 Hz, 2H), 7.81 (dd, J=2.4,8.8 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.04-7.00 (m, 3H), 6.96 (t, J=7.6Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.58 (t, J=7.6 Hz, 1H), 4.84 (bs, 2H),3.82-3.79(m, 4H), 3.44-3.40 (m, 4H). LRMS: (calcd.) 440.4; (found.)441.4 (MH)⁺.

Example 129N-(2-Amino-phenyl)-4-({3-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-4-methoxy-phenylamino}-methyl)-benzamide(239) Step 1:N-(2-Amino-phenyl)-4-({3-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-4-methoxy-phenylamino}-methyl)-benzamide(239)

To a solution ofN-(2-amino-phenyl)-4-[(3-hydroxy-4-methoxy-phenylamino)methyl]-benzamide(212e) (586 mg, 0.66 mmol) in DMF (10 ml) were added2-(3-bromopropyl)-isoindole-1,3-dione (238) (176 mg, 0.66 mmol) andK₂CO₃ (365 mg, 2.64 mmol) at room temperature. The reaction mixture washeated at 100° C. for 1 h then overnight at 60° C., cooled, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(eluent from AcOEt-hexane (40:60) to pure AcOEt) to afford 239 (168 mg,46% yield). ¹H NMR: (DMSO) δ (ppm): 9.57 (bs, 1H), 7.88 (d, J=8.0 Hz,2H), 7.84-7.75 (m, 4H), 7.44 (d, J=8.0 Hz, 2H), 7.12 (d, J=7.2 Hz, 1H),6.92 (t, J=8.8 Hz, 1H), 6.75 (dd, J=1.2, 7.6 Hz, 1H), 6.57 (d, J=8.4 Hz,2H), 6.27 (d, J=2.4 Hz, 1H), 6.00-5.93 (m, 2H), 4.87 (s, 2H), 4.27 (d,J=6.0 Hz, 2H), 3.89 (dd, J=5.6, 6.0 Hz, 2H), 3.74 (dd, J=6.4, 6.8 Hz,2H), 3.42 (s, 3H), 2.06-2.01 (m, 2H). LRMS: (calcd.) 550.4; (found.)551.5 (MH)⁺.

Example 130 4-[1-(6-Acetyl-benzo [1,3]dioxol-5-ylamino)-ethyl]-N-(2-amino-phenyl)-benzamide (240)

Title compound 240 was prepared using the same procedures as describedfor the compound 212a, example 99 (scheme 42, table 1), starting from1-(6-amino-benzo[1,3]dioxol-5-yl)-ethanone and 4-acetylbenzoic acid(scheme 51). ¹H NMR: (DMSO-d₆) δ(ppm): 8.69 (s, 1H), 7.03 (d, J=7.8 Hz,2H), 6.64 (d, J=7.8 Hz, 2H), 6.29 (dd, J=8.3, 7.8 Hz, 1H), 6.09 (t,J=7.8, 7.3 Hz, 1H), 5.90 (d, J=7.8, 1H), 5.72 (d, J=6.8 Hz, 1H), 5.70(s, 1H), 5.16 (d, J=8.8 Hz, 1H), 4.88 (s, 1H), 4.84 (s, 1H), 4.07 (bd,1H), 2.30 (s, 3H), 0.62 (d, J=6.83, 3H).

Example 131N-(2-Amino-phenyl)-4-{[4,5-dimethoxy-2-(3,4,5-trimethoxy-benzoyl)-phenylamino]-methyl}-benzamide(245) Step 1:(4,5-Dimethoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanol (241)

A flame-dried round-bottomed flask under N₂ atmosphere was charged with5-iodo-1,2,3-trimethoxybenzene (2.92 g, 9.93 mmol) and THF (31 mL) wasadded. The solution was cooled down to −78° C. and 1.5 M solution oft-BuLi in pentane (13.6 mL, 20.57 mmol) was added dropwise. The mixturewas stirred for 1 h and transferred via canula to a precooled (−78° C.)solution of 6-nitroveratraldehyde (2.02 g, 9.57 mmol) in THF (12 mL)under N₂ atmosphere. The resulting mixture was stirred for 2 h andslowly warmed up to 0° C., quenched with saturated aqueous solution ofNH₄Cl and allowed to warm-up to rt. Solvent was removed in vacuo and theresidue was partitioned between water and DCM. Organic layer wascollected and washed with brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash chromatography using EtOAc/DCM(9:91) affording the title compound 241 (1.46 g, 40% yield) ¹H NMR(CDCl₃) δ (ppm): 7.61 (s, 1H), 7.16 (s, 1H), 6.58 (s, 2H), 6.45 (s, 1H),6.09 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.83 (s, 6H).m/z: 402.4 (MH⁺).

Step 2:(4,5-Dimethoxy-2-nitro-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (242)

Powdered 4 Å molecular sieves (583 mg) and pyridinium dichromate (2.17g, 5.77 mmol) were successively added to a stirred solution ofintermediate 241 (1.46 g, 3.84 mmol) in of anhydrous DCM (38.5 mL) at 0°C. The mixture was stirred at rt for 15 h. More PDC (290 mg, 0.770 mmol)was added and the mixture was stirred for another 4 h, The diluted withether and filtered through a celite pad. The filtrate was concentratedand the brown solid was purified by flash chromatography using EtOAc/DCM(7:93) affording the title compound 242 (551 mg, 41%) as a yellow solid.¹H NMR (CDCl₃) δ (ppm): 7.72 (s, 1H), 6.99 (s, 2H), 6.86 (s, 1H), 4.06(s, 3H), 4.00 (s, 3H), 3.93 (s, 3H), 3.84 (s, 6H). m/z: 378.4 (MH⁺).

Step 3:(2-Amino-4,5-dimethoxy-phenyl)-(3,4,5-trimethoxy-phenyl)-methanone (243)

Iron powder (653 mg, 11.7 mmol) was added to a suspension ofintermediate 199 (552 mg, 1.46 mmol) in a mixture of EtOH (5.11 mL), H₂O(2.56 mL) and AcOH (5.11 mL) and 2 drops of concentrated HCl were addedto the solution. The mixture was vigorously stirred while refluxing for1 h, cooled down to rt and filtered through a celite pad. The filtratewas concentrated in vacuo and the aqueous residue partitioned betweenDCM and H₂O. The organic layer was washed with sat. NaHCO₃, dried overNa₂SO₄ and concentrated in vacuo affording the title compound 243 (393mg, 77%). ¹H NMR (CDCl₃) δ (ppm): 7.00 (s, 1H), 6.88 (s, 2H), 6.23 (s,1H), 3.92 (m, 6H), 3.88 (s, 6H), 3.70 (s, 3H). m/z: 348.4 (MH⁺).

Step 4:4-{[4,5-Dimethoxy-2-(3,4,5-trimethoxy-benzoyl)-phenylamino]-methyl}-benzoicacid (244)

The title compound 244 was obtained following same procedure as for thereductive amination described in scheme 3, step 2 (example 12) startingfrom compound 243 (46% yield). m/z: 482.5 (MH⁺).

Step 5:N-(2-Amino-phenyl)-4-{[4,5-dimethoxy-2-(3,4,5-trimethoxy-benzoyl)-phenylamino]-methyl}-benzamide(245)

The title compound 245 was obtained following the same procedure as forthe BOP coupling described in scheme 1, step 5 (example 1) usingcompound 244 as starting material. (38% yield). ¹H NMR: (DMSO-d₆)δ(ppm): 9.61 (s, 1H), 9.24 (t, J=5.7 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H),7.51 (d, J=8.2 Hz, 2H) 7.13 (d, J=8.0 Hz, 1H), 6.98 (s, 1H), 6.94 (td,J=7.6, 1.2 Hz, 1H) 6.84 (s, 2H), 6.75 (dd, J=8.0, 1.3 Hz, 1H), 6.57 (t,J=7.2 Hz, 1H), 6.35 (s, 1H), 4.89 (s, 2H), 4.62 (d, J=5.7 Hz, 2H), 3.79(s, 6H), 3.76 (s, 3H), 3.73 (s, 3H), 3.54 (s, 3H). m/z: 572.5 (MH⁺).

Example 132N-(2-Amino-phenyl)-4-{[4,5-dimethoxy-2-(4-methoxy-benzoyl)-phenylamino]-methyl}-benzamide(246)

The title compound 246 was obtained following the same proceduresdescribed in example 131 but substituting the organolithium reagentobtained from 5-iodo-1,2,3-trimethoxybenzene and t-BuLi for thecommercially available Grignard reagent 4-methoxyphenyl magnesiumbromide (8.4% overall yield). ¹H NMR: (DMSO-d₆) δ(ppm): 9.62 (s, 1H),9.10 (t, J=5.7 Hz, 1H), 7.95 (d, J=8.2, 2H), 7.57 (d, J=8.8 Hz, 2H),7.52 (d, J=8.2 Hz, 2H), 7.14 (d, J=6.6 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H),6.95 (td, J=8.2, 1.6 Hz, 2H), 6.94 (s, 1H), 6.76 (dd, J=7.8, 1.4 Hz,1H), 6.58 (t, J=6.5 Hz, 2H), 6.35 (s, 2H), 4.90 (s, 2H), 4.62 (d, J=5.3Hz, 2H), 3.84 (s, 3H), 3.76 (s, 3H), 3.54 (s, 3H). m/z: 512.6 (MH⁺).

Example 133N-(2-Amino-phenyl)-4-[(1-methyl-1H-benzoimidazol-5-ylamino)-methyl]-benzamide(252) Step 1. N1-Methyl-4-nitro-benzene-1,2-diamine (248)

A solution of fluoride 247 (5.41 g, 34.7 mmol) in DMF (40 mL) wastreated with 40% w/w solution of MeNH₂ in water (10 mL, 128 mmol). Themixture stirred at 90° C. for 3 h, diluted with EtOAc, washed withsaturated aqueous NaHCO₃. Organic phase was dried over MgSO₄, evaporatedand the residue was purified by flash chromatography (eluent 50% EtOAcin CH₂Cl₂) to afford compound 248 (5.31 g, 92% yield). ¹H NMR: (CDCl₃) δ(ppm): 7.75 (dd, J=2.6, 8.8 Hz, 1H), 7.53 (d, J=2.6 Hz, 1H), 6.45 (d,J=8.8 Hz, 1H), 4.24 (bs, 3H), 2.91 (s, 3H). LRMS: (calcd.) 167.2;(found) 168.1 (MH)⁺.

Step 2. 1-Methyl-5-nitro-1H-benzoimidazole (249)

To a suspension of diamine 248 (1.14 g, 6.80 mmol) in CH₂Cl₂ (10 mL) wasadded trimethyl orthoformate (5 mL, 46 mmol, 6.7 eq) (or any otheracylating agent of choice, 6 eq) followed by TFA (0.43 mL, 5.6 mmol, 0.8eq) and the mixture was stirred at room temperature for 2 h. Precipitatewas collected by filtration, washed with CH₂Cl₂ and dried to afford thetitle compound 249 as TFA salt (1.23 g, 62% yield). ¹H NMR: (CDCl₃) δ(ppm): 8.57 (d, J=1.8 Hz, 1H), 8.20 (dd, J=1.8, 9.2 Hz, 1H), 8.18 (s,1H), 7.54 (d, J=9.2 Hz, 1H), 3.94 (s, 3H). LRMS: (calc.) 177.2; (obt.)178.1 (MH)⁺.

Step 3. 1-Methyl-1H-benzoimidazol-5-ylamine (250)

Title compound 250 was obtained by catalytic hydrogenation of nitrocompound 249 following the procedure described in the scheme 25, step 2(example 64). LRMS: (calc.) 147.2; (obt.) 148.1 (MH)⁺.

Step 4: 4-[(1-Methyl-1H-benzoimidazol-5-ylamino)-methyl]-benzoic acid(251)

Title compound 251 was obtained by reacting the amine 250 with4-formyl-benzoic acid, following the procedure described in the scheme3, step 2 (example 12). ¹H NMR, (DMSO) δ (ppm): 8.24 (s, 1H), 7.89 (d,J=7.9 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 7.35 (d, J=8.9 Hz, 1H), 6.80 (d,J=8.9 Hz, 1H), 6.61 (s, 1H), 4.39 (s, 2H), 3.77 (s, 3H). LRMS: (calc.)281.3; (obt.) 282.3 (MH)⁺.

Step 5:N-(2-Amino-phenyl)-4-[(1-methyl-1H-benzoimidazol-5-ylamino)-methyl]-benzamide(255)

Title compound 252 was obtained by coupling of acid 251 with1,2-phenylenediamine following the procedure described in the scheme 1,step 5 (example 1). ¹H NMR: (DMSO) δ (ppm): 9.57 (s, 1H), 8.00 (s, 1H),7.91 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 1H),7.15 (d, J=7.5 Hz, 1H), 6.96 (t, J=7.5 Hz, 1H), 6.76 (m, 2H), 6.62 (s,1H), 6.57 (d, J=7.5 Hz, 1H), 6.17 (bs, 1H), 5.01 (bs, 2H), 4.40 (s, 2H),3.73 (s, 3H). LRMS: (calc.) 371.4; (obt.) 372.4 (MH)⁺.

Examples 134-140

Examples 134-140 (compounds 253-259) were prepared similarly to theexample 134 (compound 252) according to the scheme 53 substitutingtrimethyl orthoformate by corresponding acyl chlorides. TABLE 9Characterization of compounds prepared as example 133 (scheme 53)

Ex. Cmpd R Name Characterization Scheme 134 252 Me N-(2-Amino-phenyl)-4-[(1,2-dimethyl-1H- benzoimidazol-5- ylamino)-methyl]- benzamide ¹H NMR:(DMSO) δ (ppm): 9.50 (s, 1H), 7.92 (d, J=7.9 Hz, 2H), 7.50 (d, J=7.9 Hz,2H), 7.31 (d, J=8.8 Hz, 1H), 7.15 (d, J=7.4 Hz, 1H), 6.96 (t, J=7.5 Hz,1H), 6.74 (m, 2H), 6.59 (m, 2H), 6.30 (bs, 1H), 5.00 (bs, 2H), 4.40 (s,2H), 3.68 (s, 3H), 2.49 (s, 3H). LRMS: (calc.) 385.5; # (obt.) 386.4(MH)⁺. 53 135 254 MeOCH₂ N-(2-Amino-phenyl)-4- [(2-methoxy-methyl-1-methyl-1H- benzoimidazol-5- ylamino)-methyl]-benzamide ¹H NMR: (DMSO) δ(ppm): 9.57 (s, 1H), 7.91 (d, J=7.9 Hz, 2H), 7.51 (d, J=7.9 Hz, 2H),7.25 (d, J=8.8 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H), 6.96 (t, J=7.9 Hz, 1H),6.73 (m, 2H), 6.59 (m, 2H), 6.14 (bs, 1H), 4.96 (bs, 2H), 4.57 (bs, 2H),4.38 (s, 2H), 3.68 (s, 3H), # 3.27 (s, 3H). LRMS: (caic.) 415.5; (obt.)416.5 (MH)⁺. 53 136 255 CF₃ N-(2-Amino-phenyl)-4- [(1-methyl-2-trifluoromethyl-1H- benzoimidazol-5- ylamino)-methyl]- benzamide ¹H NMR:(DMSO) δ (ppm): 9.57 (s, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.2,2H), 7.46 (d, J=8.6 Hz, 1H), 7.12 (d, J=6.6 Hz, 1H), 6.96-6.92 (m, 2H),6.75 (dd, J=1.6, 8.2 Hz, 1H), 6.64 (d, J=2.0 Hz, 1H), 6.56 (ddd, J=1.6,7.4, 7.8 Hz, 1H), 6.45 # (t, J =6.2 Hz, 1H), 4.88 (bs, 2H), 4.40 (d,J=5.9 Hz, 2H), 3.85 (d, J=0.8 Hz, 3H), LRMS: (calc.) 339.4; (obt.) 440.5(MH)⁺. 53 137 256

N-(2-Amino-phenyl)-4- {[2-(3,4-dimethoxy- phenyl)-1-methyl-1H-benzoimidazol-5- ylamino]-methyl}- benzamide ¹H NMR: (DMSO) δ (ppm):9.58 (s, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.32-7.27(m, 3H), 7.14 (d, J=7.5 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.95 (t, J=7.5,1H), 6.77-6.73 (m, 2H), 6.62 (s, 1H), 6.58 (t, J=8.0, 1H), # 6.16 (bs,1H), 4.87 (bs, 2H), 4.40 (d, J=4.5, 2H), 3.83 (s, 3H), 3.81 (s, 3H),3.77 (s, 3H). LRMS: (calc.) 507.6; (obt.) 508.4 (MH)⁺. 53 138 257

N-(2-Amino-phenyl)-4- {[1-methyl-2-(3,4,5- trimethoxy-phenyl)-1H-benzoimidazol-5- ylamino]-methyl}- benzamide ¹H NMR: (DMSO) δ (ppm):9.58 (s, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.34 (d,J=9.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 7.03 (s, 2H), 6.95 (t, J=8.0,1H), 6.77 (m, 2H), 6.62 (s, 1H), 6.58 (t, J=7.0, 1H), 6.27 (bs, 1H), #4.41 (bs, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.73 (s, 3H). LRMS: (calc.)537.6; (obt.) 538.5 (MH)⁺. 139 258

N-(2-Amino-phenyl)-4- {[2-(5-bromo-pyridin 3-yl)-1-methyl-1H-benzoimidazol-5- ylamino]-methyl}- benzamide ¹H NMR: (DMSO) δ (ppm):9.58 (s, 1H), 8.97 (s, 1H), 8.82 (s, 1H), 8.44 (s, 1H), 7.92 (d, J=7.0Hz, 2H), 7.52 (d, J=7.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.14 (d, J=7.5Hz, 1H), 6.95 (m, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 # Hz, 1H),6.64 (s, 1H), 6.57 (m, 1H), 6.27 (s, 1H), 4.87 (bs, 2H), 4.41 (d, J=5.5,2H), 3.83 (s, 3H) LRMS: (calc.) 527.4; (obt.) 528.3 (MH)⁺. 53 140 259

N-(2-Amino-phenyl)-4- [(1-methyl-2-pyridin-3- yl-1H-benzoimidazol-5-ylamino)-methyl]- benzamide ¹H NMR: (DMSO) δ (ppm): 9.57 (s, 1H), 8.98(s, 1H), 8.69 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.92 (d, J=8.0 Hz, 2H),7.57 (m, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 1H), 7.15 (d,J=7.5 Hz, 1H), 6.95 (t, J=7.5 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), # 1H),6.76 (d, J =8.0 Hz, 2H), 6.66 (s, 1H), 6.58 (t, J=7.5, 1H), 6.27 (bs,1H), 4.90 (bs, 2H), 4.42 (bs, 2H), 3.81 (s, 3H) LRMS: (calc.) 448.52;(obt.) 449.2 (MH)⁺.

Example 141N-(2-Amino-phenyl)-4-(benzothiazol-6-ylaminomethyl)-benzamide (263)

Step 1. Benzothiazol-6-ylamine (261)

Title compound 261 was obtained by reducing the nitro compound 260 withtin(II) chloride following the procedure described in the scheme 33,compound 143 (example 79). LRMS: (calc.) 150.2; (obt.) 151.1 (MH)⁺.

Step 2: 4-(Benzothiazol-6-ylaminomethyl)-benzoic acid (262)

Title compound 262 was obtained by reacting amine 261 with4-formyl-benzoic acid, following the procedure described in the scheme3, step 2 (example 12). ¹H NMR, (DMSO) δ (ppm): 8.04 (s, 1H), 7.90 (d,J=8.1 Hz, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.07 (d,J=1.8 Hz, 1H), 6.89 (dd, J=1.8, 8.1 Hz, 1H), 4.42 (s, 2H). LRMS: (calc.)284.3; (obt.) 285.2 (MH)⁺.

Step 3: (2-Amino-phenyl)-4-(benzothiazol-6-ylaminomethyl)-benzamide(263)

Title compound 263 was obtained by coupling of acid 262 with1,2-phenylenediamine following the procedure described in the scheme 1,step 5 (example 1). ¹H NMR: (DMSO) δ (ppm): 9.59 (s, 1H), 8.89 (s, 1H),7.93 (d, J=8.0 Hz, 2H), 7.75 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H),7.14 (d, J=7.5 Hz, 1H), 7.08 (s, 1H), 6.96 (t, J=7.5 Hz, 1H), 6.90 (d,J=8.0 Hz, 1H), 6.76 (m, 2H), 6.58 (s, 1H), 4.87 (bs, 2H), 4.43 (bs, 2H).LRMS: (calc.) 374.5; (obt.) 375.4 (MH)⁺.

Example 142N-(2-Amino-phenyl)-4-[(1-methyl-1H-benzotriazol-5-ylamino)-methyl]-benzamide(267) Step 1: 1-Methyl-5-nitro-1H-benzotriazole (264)

A stirred suspension of diamine 248 (1.13 g, 6.76 mmol) and concentratedHCl (5.6 mL, 67 mmol) in water (22 mL) at 0° C., was treated with asolution of NaNO₂ (586 mg, 8.5 mmol) in water (10 mL). The mixture wasstirred at the same conditions for 3 h, warmed to room temperature,neutralized with a 5% w/v solution of KOH in water and filtered. Thesolid was washed with cold water and dried to afford title compound 264(975 mg, 81% yield). ¹H NMR: (DMSO) δ (ppm): 9.00 (d, J=1.3 Hz, 1H),8.39 (dd, J=1.3, 8.8 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 4.40 (s, 3H).

Step 2: 1-Methyl-1H-benzotriazol-5-ylamine (265)

Title compound 265 was obtained by reduction of the nitro compound 264with tin(II) chloride, following the same procedure described in thescheme 33, compound 143 (example 79). ¹H NMR: (CD₃OD) δ (ppm): 7.32 (d,J=8.8 Hz, 1H), 7.14 (d, J=1.7 Hz, 1H), 6.99 (dd, J=1.7, 8.8 Hz, 1H),4.21 (s, 3H). LRMS: (calc.) 148.3; (obt.) 149.3 (MH)⁺.

Step 3: 4-[(1-Methyl-1H-benzotriazol-5-ylamino)-methyl]-benzoic acid(266)

Title compound 266 was obtained by reacting amine 265 with4-formyl-benzoic acid, following the procedure described in the scheme3, step 2 (example 12). LRMS: (calc.) 282.3; (obt.) 283.3 (MH)⁺.

Step 4:N-(2-Amino-phenyl)-4-[(1-methyl-1H-benzotriazol-5-ylamino)-methyl]-benzamide(267)

Title compound 267 was obtained by coupling of acid 266 with1,2-phenylenediamine following the procedure described in the scheme 1,step 5 (example 1). ¹H NMR: (DMSO) δ (ppm): 9.58 (s, 1H), 7.92 (d, J=8.0Hz, 2H), 7.53 (m, 3H), 7.14 (d, J=8.0 Hz, 1H), 7.07 (dd, J=2.0, 8.5 Hz,1H), 6.95 (t, J=7.5 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.68 (s, 1H), 6.61(s, 2H), 4.87 (bs, 2H), 4.42 (d, J=6.0 Hz, 2H), 4.16 (s, 3H). LRMS:(calc.) 372.4; (obt.) 373.5 (MH)⁺.

Example 143N-(2-Amino-phenyl)-4-[(1-methyl-2-methylamino-1H-benzoimidazol-5-ylamino)-methyl]-benzamide(271) Step 1: Methyl-(1-methyl-5-nitro-1H-benzoimidazol-2-yl)-amine(268)

A solution of diamine 248 (1.88 g, 11.2 mmol) in pyridine (20 mL) wastreated with methyl isothiocyanate (970 mg, 12.9 mmol) and the mixturewas stirred at 80° C. for 30 minutes, cooled down to 15° C., treatedwith solid EDC (3.03 g, 15.8 mmol, 1.40 eq) and the heating continued at80° C. for 16 h. After removal of pyridine in vacuo, the residue waspurified by flash chromatography (eluent 5% MeOH in CH₂Cl₂) to affordthe title compound 268 (1.44 g, 62% yield). ¹H NMR: (CD₃OD) δ (ppm):8.12 (d, J=2.2 Hz, 1H), 7.94 (dd, J=2.2, 8.8 Hz, 1H), 7.04 (d, J=8.8 Hz,1H), 4.44 (bs, 2H), 3.51 (s, 3H), 3.04 (s, 3H). LRMS: (calc.) 206.2;(obt.) 207.1 (MH)⁺.

Step 2: Methyl-(1-methyl-5-amino-1H-benzoimidazol-2-yl)-amine (269)

Title compound 269 was obtained by catalytic hydrogenation of the nitrocompound 268, following the procedure described in the scheme 25, step 2(example 64). ¹H NMR: (CDCl₃) δ (ppm): 6.70 (s, 1H), 6.62 (d, J=7.9 Hz,1H), 6.29 (d, J=7.9 Hz, 1H), 5.97 (bs, 1H), 3.63 (bs, 2H), 3.15 (s, 3H),2.90 (s, 3H). LRMS: (calc.) 176.2; (obt.) 177.3 (MH)⁺.

Step 3:4-[(1-Methyl-2-methylamino-1H-benzoimidazol-5-ylamino)-methyl]-benzoicacid (270)

Title compound 270 was obtained by reacting the amine 269 with4-formyl-benzoic acid with, following the procedure described in thescheme 3, step 2 (example 12). ¹H NMR: (DMSO) δ (ppm): 8.03 (bs, 1H),7.88 (d, J=7.9 Hz, 2H), 7.47 (d, J=7.9 Hz, 2H), 7.02 (d, J=8.3 Hz, 1H),6.46 (d, J=8.3 Hz, 1H), 6.44 (s, 1H), 4.35 (bs, 2H), 3.43 (s, 3H), 2.90(d, J=3.5 Hz, 3H). LRMS: (calc.) 310.3; (obt.) 311.4 (MH)⁺.

Step 4:N-(2-Amino-phenyl)-4-[(1-methyl-2-methylamino-1H-benzoimidazol-5-ylamino)-methyl]-benzamide(271)

Title compound 271 was obtained by coupling of the acid 270 with1,2-phenylenediamine following the procedure described in the scheme 1,step 5 (example 1). ¹H NMR: (DMSO) δ (ppm): 9.56 (s, 1H), 7.90 (d, J=7.9Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 7.15 (d, J=7.5 Hz, 1H), 6.80 (d, J=8.4Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 6.58 (t, J=7.5 Hz, 1H), 6.39 (s, 1H),6.31 (m, 2H), 5.75 (t, J=5.7 Hz, 1H), 4.87 (s, 2H), 4.32 (d, J=5.7 Hz,2H), 3.34 (s, 3H), 2.82 (d, J=4.4 Hz, 3H). LRMS: (calc.) 400.5; (obt.)401.5 (MH)⁺

Example 144 N-(2-Amino-phenyl)-4-(quinoxalin-6-ylaminomethyl)-benzamide(276) Step 1: 6-Nitro-quinoxaline (273)

A solution of nitroaniline 272 (1.04 g, 6.76 mmol) in 2-propanol (35 mL)was treated with 40% aqueous glyoxal (0.85 mL, 7.4 mmol, 1.1 eq.) (orany other 1,2-dicarbonyl compound, 1.1 eq). The mixture was stirred at80° C. for 2 h and concentrated in vacuo to afford the title compound273, which was used for the next step without further purification.LRMS: (calc.) 175.1; (obt.) 176.1 (MH)⁺.

Step 2: Quinoxalin-6-ylamine (274)

Title compound 274 was obtained by reduction of the nitro compound 273with tin(II) chloride following the same procedure described in thescheme 33, compound 143 (example 79). LRMS: (calc.) 145.2; (obt.) 146.2(MH)⁺.

Step 3: 4-(Quinoxalin-6-ylaminomethyl)-benzoic acid (275)

Title compound 275 was obtained by reacting the amine 274 with4-formyl-benzoic acid, following the procedures described in the scheme3, step 2 (example 12). LRMS: (calc.) 279.3; (obt.) 280.2 (MH)⁺.

Step 4: N-(2-Amino-phenyl)-4-(quinoxalin-6-ylaminomethyl)-benzamide(276)

Title compound 276 was obtained by coupling of acid 275 with1,2-phenylenediamine following the procedure described in the scheme 1,step 5 (example 1). ¹H NMR: (DMSO) δ (ppm): 9.61 (s, 1H), 8.56 (d, J=2.0Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.75 (d, J=9.0Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.40-7.36 (m, 2H), 7.13 (dd, J=1.6, 6.8Hz, 1H), 6.95 (dt, J=1.6, 8.0 Hz, 1H), 6.76 (dd, J=1.2, 7.8 Hz, 1H),6.67 (d, J=2.5 Hz, 1H), 6.59 (dd, J=1.2, 7.8 Hz, 1H), 5.05 (bs, 2H),4.53 (d, J=5.7 Hz, 2H). LRMS: (calc.) 369.4; (obt.) 370.4 (MH)⁺.

Example 145N-(2-Amino-phenyl)-4-[(2,3-di-pyridin-2-yl-quinoxalin-6-ylamino)-methyl]-benzamide(277)

Title compound was prepared following the procedures depicted in scheme57 for example 144 using in the first step1,2-di-pyridin-2-yl-ethane-1,2-dione instead of glyoxal.

¹H NMR: (DMSO) δ (ppm): 9.57 (s, 1H), 8.21 (m, 1H), 8.17 (m, 1H), 7.94(d, J=8.0 Hz, 2H), 7.89-7.84 (m, 3H), 7.80 (dt, J=1.8, 7.6 Hz, 1H), 7.55(m, 3H), 7.46 (dd, J=2.3, 9.0 Hz, 1H), 7.29-7.22 (m, 2H), 7.12 (d, J=7.6Hz, 1H), 6.92 (m, 1H), 6.78 (d, J=2.3 Hz, 1H), 6.75 (dd, J=1.4, 8.3 Hz,1H), 6.56 (t, J=7.6 Hz, 1H), 4.87 (bs, 2H), 4.58 (d, J=6.1 Hz, 2H), 4.34(d, J=4.3 Hz, 1H). LRMS: (calc.) 523.6; (obt.) 524.5 (MH)⁺.

Example 1464-((2-(2-(dimethylamino)ethyl)-1,3-dioxoisoindolin-6-ylamino)methyl)-N-(2-aminophenyl)benzamide(278)

Step 1. 2-(2-(dimethylamino)ethyl)-5-nitroisoindoline-1,3-dione (280)

A solution of nitroftalic anhydride (279) (995 mg; 5.2 mmol) in aceticacid (12 mL) was treated with neat N1,N1-dimethylethane-1,2-diamine(0.75 mL; 5.8 mmol; 1.13 eq.) (or the corresponding amine, 1.3 eq.). Thereaction mixture was stirred for 3 h at 100° C., cooled down to roomtemperature, concentrated in vacuo; the residue was dissolved in ethylacetate (250 mL) and washed with saturated NaHCO₃, dried over MgSO₄,filtered and concentrated, to yield compound 280 as a yellow solid (1.19g; 4.5 mmol; 87%). LRMS: 263.3 (calc.); 264.2 (obt.) (MH)⁺.

Step 2. 5-amino-2-(2-(dimethylamino)ethyl)isoindoline-1,3-dione (281)

Title compound 281 was obtained by catalytic hydrogenation of the nitrocompound 280 following the procedure described in the scheme 25, step 2(example 64). LRMS: 233.3 (calc.); 234.2 (obt.) (MH)⁺.

Step 3.4-((2-(2-(dimethylamino)ethyl)-1,3-dioxoisoindolin-6-ylamino)methyl)benzoicacid (282)

Title compound 282 was obtained by reacting the amine 281 with4-formyl-benzoic acid, following the procedure described in the scheme3, step 2 (example 12). ¹H NMR, (DMSO) δ (ppm): 7.89 (d, J=8.2 Hz, 2H),7.78 (t, J=6.1 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.43 (d, J=8.2 Hz, 2H),6.91 (s, 1H), 4.53 (d, J=6.1 Hz, 2H), 3.80 (t, J=5.5 Hz, 2H), 3.32 (bs,2H), 3.21 (bs, 2H), 2.74 (s, 6H). LRMS: 367.4 (calc.); 368.4 (obt.)(MH)⁺.

Step 4.4-((2-(2-(dimethylamino)ethyl)-1,3-dioxoisoindolin-6-ylamino)methyl)-N-(2-aminophenyl)benzamide(278)

Title compound 278 was obtained by coupling of acid 282 with1,2-phenylenediamine following the procedure described in the scheme 1,step 5 (example 1). ¹H NMR: (DMSO) δ (ppm): 9.52 (s, 1H), 7.85 (d, J=8.0Hz, 2H), 7.63 (t, J=5.9 Hz, 1H), 7.42 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2Hz, 2H), 7.05 (d, J=7.2 Hz, 1H), 6.87 (d, J=7.2 Hz, 1H), 6.82 (s, 1H),6.76 (d, J=8.2 Hz, 2H), 6.67 (d, J=7.8 Hz, 1H), 6.49 (t, J=7.2 Hz, 1H),4.81 (s, 2H), 4.45 (d, J=5.9 Hz, 2H), 3.48 (t, J=6.3 Hz, 2H), 2.32 (t,J=6.3 Hz, 2H), 2.04 (s, 6H). LRMS: (calc.) 457.5; (obt.) 458.5 (MH)⁺.

Example 147N-(2-Amino-phenyl)-4-[(1,3-dioxo-2-pyridin-3-ylmethyl-2,3-dihydro-1H-isoindol-5-ylamino)-methyl]-benzamide(283)

Title compound was prepared according to the reaction sequence depictedin scheme 58 for example 146, but using in the first step3-aminomethylpyridine instead of N,N-dimethyl ethylenediamine.

283: Example 147

¹H NMR: (DMSO) δ (ppm): 9.60 (s, 1H), 8.50 (s, 1H), 8.44 (t, J=3.7 Hz,1H), 7.92 (d, J=8.0 Hz, 2H), 7.76 (t, J=6.3 Hz, 1H), 7.62 (dt, J=2.0,3.9 Hz, 2H), 7.54 (d, J=8.2 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.31 (dd,J=4.7, 7.6 Hz, 1H), 7.12 (d, J=6.6 Hz, 1H), 6.97-6.93 (m, 2H), 6.85 (d,J=8.4 Hz, 1H), 6.75 (dd, J=1.4, 8.0 Hz, 1H), 6.58 (dt, J=1.4, 7.6 Hz,1H), 4.96 (bs, 2H), 4.70 (s, 2H), 4.53 (d, J=6.3 Hz, 2H), LRMS: (calc.)477.5; (obt.) 478.5 (MH)⁺. TABLE 10 Characterization of examples 148-177(compounds 284-313) prepared according to the schemes 19-30. Ex CmpdStructure Name Characterization 148 284

N-(2-Amino- phenyl)-4-(2-oxo-2- piperidin-1-yl- ethyl)-benzamide ¹H NMR:(DMSO) δ (ppm): 9.61 (bs, 1H), 7.90 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2Hz, 2H), 7.14 (d, J=7.6 Hz, 1H), 6.95 (ddd, J=7.6, 7.6, 1.5 Hz, 1H),6.76 (dd, J=8.0, 1.2 Hz, 1H), 6.58 (ddd, J=7.4, 7.4, 1.2 Hz, 1H), 4.89(s, 2H), 3.78 (s, 2H), 3.44-3.42 (m, 4H), 1.56-1.54 (m, 2H), # 1.41-1.36(m, 4H). MS: (calc.) 337.2; (obt.) 338.4 (MH)⁺. 149 285

N-(2-Amino- phenyl)-4-{2-[4-(4- methoxy-phenyl)- piperazin-1-yl]-2-oxo-ethyl}- benzamide ¹H NMR: (DMSO) δ (ppm): 9.60 (s, 1H), 7.88 (d,J=8.0 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 7.11 (d, J=7.8 Hz, 1H), 6.93 (dd,J=7.6, 7.6 Hz, 1H), 6.86 (d, J=9.0 Hz, 2H), 6.78 (d, J =9.0 Hz, 2H),6.74 (d, J =7.8 Hz, 1H), 6.55 (dd, J=7.4, 7.4 Hz, # 1H), 4.88 (s,2H),3.83 (s,2H), 3.65 (s,3H), 3.62-3.58 (m, 4H), 2.96-2.90 (m, 4H). MS:(calc.) 444.2; (obt.) 445.4 (MH)⁺. 150 286

N-(2-Amino- phenyl)-4-[2-oxo-2- (4-pyrimidin-2-yl- piperazin-1-yl)-ethyl]-benzamide ¹H NMR: (DMSO) δ (ppm): 9.62 (s, 1H), 8.36 (d, J=4.7Hz, 2H), 7.90 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.2 Hz, 2H), 7.13 (d, J=6.8Hz, 1H), 6.95 (ddd, J=7.5, 7.5, 1.4 Hz, 1H), 6.76 (dd, J=8.0, 1.4 Hz,1H), 6.70 (t, J=4.8 Hz, 1H), 6.57 (ddd, J=7.6, 7.6, # 1.4 Hz, 1H), 4.90(s, 2H), 3.87 (s, 2H), 3.72-3.68 (m, 4H), 3.62-3.55 (m, 4H). MS: (calc.)416.2; (obt.) 417.4 (MH)⁻. 151 287

N-(2-Amino- phenyl)-4-{2-[4-(4- fluoro-benzoyl)- piperidin-1-yl]-2-oxo-ethyl}- benzamide ¹H NMR: (DMSO) δ (ppm): 9.62 (s, 1H), 8.08-8.04(m, 2H), 7.91 (d, J=8.0 Hz, 2H), 7.37-7.33 (m, 4H), 7.15 (d, J=7.2 Hz,1H), 6.95 (ddd, J=7.5, 7.5, 1.4 Hz, 1H), 6.76 (dd, J=8.0, 1.4 Hz, 1H),6.58 (ddd, J=7.6, 7.6, 1.4 Hz, 1H), 4.89 (s, 2H), 4.43-4.40 # (m, 1H),4.04- 4.01 (m, 1H), 3.82 (s, 2H), 3.72-3.66 (m, 1H), 3.31- 3.15(m, 1H),1.82-1.74 (m, 2H), 1.40-1.34 (m, 2H). MS: (calc.) 459.2; (obt.) 460.5(MH)⁺. 152 288

N-(2-Amino- phenyl)-4-{2-oxo-2- [4-(5- trifluoromethyl- pyridin-2-yl)-piperazin-1-yl]- ethyl}-benzamide ¹H NMR: (DMSO) δ (ppm): 9.61 (s, 1H),8.41 (s, 1H), 7.91 (d, J=8.0 Hz, 2H), 7.80 (dd, J=9.3, 2.4 Hz, 1H), 7.36(d, J=8.4 Hz, 2H), 7.14 (d, J=7.6 Hz, 1H), 6.97-6.93 (m, 2H), 6.76 (dd,J=7.8, 1.4 Hz, 1H), 6.57 (ddd, J=7.6, 7.6, # 1.4 Hz, 1H), 4.88 (s, 2H),3.87 (s, 2H), 3.66-3.58 (m, 8H). MS: (calc.) 483.2; (obt.) 484.5 (MH)⁺.153 289

N-(2-Amino- phenyl)-4-[2-(4- benzo[1,3]dioxol-5- ylmethyl-piperazin-1-yl)-2-oxo-ethyl]- benzamide ¹H NMR: (DMSO) δ (ppm): 9.60 (s, 1H), 7.89(d, J=8.2 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 7.14 (d, J=7.6 Hz, 1H), 6.95(ddd, J=7.6, 7.6, 1.8 Hz, 1H), 6.84-6.81 (m, 2H), 6.76 (dd, J=7.8, 1.2Hz, 1H), 6.72 (dd, J=8.0, 1.6 Hz, 1H), 6.58 (ddd, J=7.4, # 7.4, 1.4 Hz,1H), 5.97 (s, 2H), 4.89 (s, 2H), 3.78 (s, 2H), 3.49-3.46 (m, 4H), 3.37(s, 2H), 2.29-2.27 (m, 4H). MS: (calc.) 372.2; (obt.) 373.5 (MH)⁺. 154290

N-(2-Amino- phenyl)-4-[2-(4- benzyl-piperidin-1- yl)-2-oxo-ethyl]-benzamide ¹H NMR: (400 MHz, DMSO-d₆,(ppm): 9.60 (s, 1H), 7.88 (d, J=8.2Hz, 2H), 7.11 - 7.31 (m, 8H), 6.94 (d (dd), J=7.0 Hz, 1H), 6.75 (t (dd),J=7.8 Hz, 1H), 6.57 (d (dd), J=7.4 Hz, 1H), 4.87 (s, 2H), 4.34 (br. d,j=12.5 Hz, 1H), 3.92 (br. d, j=13.9 Hz, 1H), 3.75 (s, 2H), # 3.32 (s,2H), 2.91 (br. t, j=11.3 Hz, 1H), 1.70- 1.74 (m, 1H), 1.51-1.56 (m, 2H),1.01-0.92 (m, 2H). 155 291

N-(2-Amino- phenyl)-4-[2-(4- cyano-4-phenyl- piperidin-1-yl)-2-oxo-ethyl]- benzamide ¹H NMR: (400 MHz, DMSO-d₆,(ppm): 9.60 (s, 1H),7.90 (d, J=8.0 Hz, 2H), 7.33-7.51 (m, 7H), 7.13 (d (dd), J=7.4 Hz, 1H),6.93 (t (dd), J=9.4 Hz, 1H), 6 74 (d (dd), J=8.0 Hz, 1H), 6.56 (t (dd),j=7.8 Hz, 1H), 4.87 (s, 2H), 4.60 (br. d, j=13.9 Hz, 1H), # 4.17 (br. d,j=14.7 Hz, 1H), 3.82-3.92 (m (instead of expected s), 2H), 3.26 (br. t,j=12.1 Hz, 1H), 2.85 (br. t, j=12.7 Hz, 1H), 2.12-2.16 (m, 2H), 1.89-1.94 (m, 2H). 156 292

N-(2-Amino- phenyl)-4-(5- methoxy-1H- benzoimidazol-2- ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 12.12 (s, 1H), 9.59 (s, 1H), 7.91 (d,J=8.2 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.35 (s, 1H), 7.14 (d, J=7.4 Hz,1H), 6.97-6.93 (m, 2H), 6.77-6.73 (m, 2H), 6.58 (dd, J=7.1, 7.1 Hz, 1H),4.87 (s, 2H), 4.21 (s, 2H), 3.75 (s, 3H). MS: (calc.) 372.2; (obt.) #373.5 (MH)⁺. 157 293

N-(2-Amino- phenyl)-4-(5-fluoro- 1H-benzoimidazol- 2-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 12.42 (s, 1H), 9.59 (s, 1H 7.91 (d,J=8.2 Hz, 2H), 7.43 (m, 3H), 7.26 (m, 1H), 7.13 (d, J=6.7 Hz, 2H),6.23-6.99 (m, 2H), 6.74 (d, J=1.4 Hz, 1H), 6.57 (dd, J=8.2, 8.2 Hz, 1H),4.87 (s, 2H), 4.24 (s, 2H), 3.16 (s, 1H). MS: (calc.) 360.1; (obt.)361.5 (MH)⁺. 158 294

N-(2-Amino- phenyl)-4-[4-cyano- 5-(2- dimethylamino- acetylamino)-thiophen-2- ylmethyl]- benzamide ¹H NMR: (DMSO) δ (ppm): 9.60 (bs, 1H),7.93 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.16 (d, J=7.3 Hz, 1H),6.99-6.93 (m, 2H), 6.77 (d, J=7.3 Hz, 1H), 6.59 (dd, J=7.3, 7.3 Hz, 1H),4.88 (bs, 2H), 4.12 (s, 2H), 3.33 (s, 2H), 2.36 (s, 6H). # MS: (calc.)432.2; (obt.) 433.5 (MH)⁻. 159 295

N-(2-Amino- phenyl)-4-[4-cyano- 5- (cyclopropanecarbo nyl-amino)-thiophen-2- ylmethyl]- benzamide ¹H NMR: (DMSO) δ (ppm): 11.85 (bs, 1H),9.61 (bs, 1H), 7.92 (d, J=7.8 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 7.15 (d,J=7.80 Hz, 1H), 6.98-6.95 (m, 2H), 7.11 (d, J =8.8 Hz, 2H), 6.99 (dd,J=7.7, 7.7 Hz, 1H), 6.77 (d, J=6.3 Hz, 1H), 6.59 (dd, # J=7.6, 7.6 Hz,1H), 4.88 (bs, 2H), 4.12 (s, 2H), 2.14-2.13 (m, 1H), 0.90-0.84 (m, 4H).MS: (calc.) 392.1; (obt.) 393.4 (MH)⁻. 160 296

5-[4-(2-Amino- phenylcarbamoyl)- benzyl]-2- propionylamino thiophene-3-carboxylic acid amide ¹H NMR: (DMSO) δ (ppm): 12.06 (s, 1H), 9.61 (s,1H), 7.92 (d, J=8.2 Hz, 1H), 7.82 (bs, 1H), 7.45 (bs, 1H), 7.37 (d,J=8.2 Hz, 1H), 7.19 (s, 1H), 7.14 (d, J=6.2 Hz, 1H), 6.95 (ddd, J=7.6,7.6, 1.6 Hz, 1H), 6.76 (dd, J=8.2, 1.6 Hz, 1H), 6.57 (ddd, # J=7.4, 7.4,1.6 Hz, 1H), 4.98 (s, 2H), 4.10 (s, 2H), 2.44 (q, J=7.6 Hz, 2H), 1.09(t, J=7.6 Hz, 2H). MS: (calc.) 422.1.; (obt.) 423.4. (MH)⁺. 161 297

N-(2-Amino- phenyl)-4-(3,5- dimethyl-pyrazol-1- ylmethyl)- benzamide ¹HNMR: (400 MHz, DMSO-d₆,(ppm): 9.59 (s, 1H), 7.92 (d, J=8.2, 2H), 7.16(d, J=8.4, 2H), 7.12 (d (dd), J=6.5, 1H), 6.94 (dd, J=1.4 Hz, j=7.8 Hz,1H), 6.75 (dd, j=1.4 Hz, j=8.0 Hz, 1H), 6.57 (dd, j=1.4 Hz, 7.4 Hz, 1H),5.86 (s, 1H), 5.26 (s, 2H), 4.88 (s, 2H), 2.16 (s, # 3H), 2.11 (s, 3H)162 298

N-(2-Amino- phenyl)-4-(6-oxo- 6H-pyrimidin-1- ylmethyl)- benzamide ¹HNMR: (DMSO) δ (ppm): 9.61 (s, 1H), 8.69 (s, 1H), 7.94-7.92 (m, 2H), 7.42(d, J=7.8 Hz, 2H), 7.12 (d, J=7.4 Hz, 1H), 6.95 (dd, J=7.2, 7.2 Hz, 1H),6.75 (d, J=7.2 Hz, 1H), 6.57 (dd, J=7.2, 7.2 Hz, 1H), 5.16 (s, 2H), 4.89(s, 2H). MS: (calc.) 320.2; (obt.) 321.5 (MH)⁻. 163 299

5-(3-Methoxy- benzylamino)- benzofuran-2 carboxylic acid (2-amino-phenyl)- amide ¹H NMR: (DMSO) δ(ppm): 9.69 (s, 1H), 7.45 (s, 1H),7.40 (d, J=6.8 Hz, 1H), 7.26-7.18 (m, 2H), 6.97- 6 73 (m, 8H), 6.60 (dd,J=7.3, 7.3 Hz, 1H), 6.22 (t, j=5.9 Hz, 1H), 4.92 (s, 2H), 4.27 (d, J=5.9Hz, 2H), 3.73 (s, 3H). MS: (calc.) 387.1; (obt.) 388.4 (MH)⁺. 164 300

5-[(Pyridin-3- ylmethyl)-amino]- benzofuran-2- carboxylic acid (2-amino-phenyl)- amide ¹H NMR: (DMSO) δ (ppm): 9.69 (s, 1H), 8.62 (s, 1H),8.44 (d, J=4.4 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.41 (d,J=8.8 Hz, 1H), 7.35 (dd, J=8.1, 5.1 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H),6.97 (dd, J=7.0, 7.0 Hz, 1H), 6.88 (dd, J=8.8, # 2.2 Hz, 1H), 6.79-6.77(m, 2H), 6.59 (dd, J=6.9, 6.9 Hz, 1H), 6.27 (t, J=5.9 Hz, 1H), 4391(s,2H), 4.33 (d, J=5.9 Hz, 1H). MS: (calc.) 358.1; (obt.) 359.4 (MH)⁺.165 301

5-[(2,4-Dimethoxy- pyrimidin-5- ylmethyl)-amino]- benzofuran-2-carboxylic acid (2- amino-phenyl)- amide ¹H NMR: (DMSO) δ (ppm): 9.70(s, 1H), 8.20 (s, 1H), 7.46 (s, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.17 (dd,J=7.8, 1.2 Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.85 (dd, J=8.9,2.3 Hz, 1H), 6.78-6.76 (m, 2H), 6.58 (ddd, J=7.5, 7.5, 1.4 Hz, 1H), #5.99 (t, J=5.8 Hz, 1H), 4.92 (s, 2H), 4.14 (d, J=5.9 Hz, 2H), 3.97 (s,3H), 3.86 (s, 3H). MS: (calc.) 419.2; (obt.) 420.5 (MH)⁺. 166 302

5-[Bis-(2,4- dimethoxy- pyrimidin-5- ylmethyl)-amino]- benzofuran-2-carboxylic acid (2-amino-phenyl)- amide ¹H NMR: (DMSO) δ (ppm): 9.72 (s,1H), 7.66 (s, 2H), 7.47-7.39 (m, 2H), 7.15 (d, J=7.0 Hz, 1H), 6.98-6.92(m, 3H), 6.75 (d, J=8.0 Hz, 1H), 6.56 (dd, J=7.5, 7.5 Hz, 1H), 4.91 (s,2H), 4.47 (s, 4H), 3.90 (s, 6H), 3.82 (s, 6H). MS: (calc.) 571.2; #(obt.) 572.5 (MH)⁺. 167 303

N-(2-Amino- phenyl)-4-[5-(3,4- dimethoxy-benzyl)- [1,2,4]oxadiazol-3-ylmethyl]- benzamide ¹H NMR: (300 MHz,DMSO-d_(6,(ppm): 9.61 (s, 1H), 7.92 (d, J=7.62, 2H), 7.42 (d, J =8.21, 2H), 7.15 (d, J=7.62, 1H), 6.99-6.89 (m, 3H), 6.83-6.76 (m, 2H), 6.59 (t, J=7.03, 1H), 4.88 (brs, 2H), 4.23 (s, 2H), 4.16 (s, 2H), 3.72 (s, 3H), 3.71 (s, 3H))168 304

5-[(4-Morpholin-4- yl-phenylamino)- methyl]-benzotfuran- 2-carboxylicacid (2-amino-phenyl)- ainide ¹ H NMR: (DMSO) δ (ppm): 9.01 (s, 1H),6.92 (s, 1H), 6.84 (s, 1H), 6.80 (d, J=8.5, 1H), 6.65 (d, J=9.0, 1H),6.36 (d, J=8.0, 1H), 6.16 (t, J=7.75, 1H), 5.96 (d, J=7.5, 1H), 5.89 (d,J =8.0, 2H), 5.77 (t, J=7.5, 1H), 5.71 (d, J=8.0, # 2H), 5.05 (m, 1H),4.12 (brs, 2H), 3.49 (brd, J=5.5, 2H), 2.87-2.83 (m, 4H), 2.06-2.02 (m,4H). MS: (calc.) 442; (obt.) 443.5 (MH)⁺. 169 305

5-[(2-Acetyl- phenylamino)- methyl]-benzofuran- 2-carboxylic acid(2-amino-phenyl)- amide ¹H NMR: (DMSO) δ (ppm): 9.85 (s, 1H), 9.26 (s,1H), 7.86 (d, J=8.0, 1H), 7.75 (s, 1H), 7.69-7.67 (m, 2H), 7.47 (d,J=8.5, 1H), 7.33 (t, J=7.75, 1H), 7.19 (d, J=7.5, 1H), 6.99 (t, J=7.75,1H), 6.78 (d, J=14.0, 1H), 6.77 (d, J=14.0, 1H), 6.62- 6.59 # (m, 2H),4.96 (s, 2H), 4.59 (d, J=5.5, 2H), 2.57 (s, 3H). MS: (calc.) 399; (obt.)400.2 (MH)⁺. 170 306

5-[(3,4-Dimethoxy- phenylamino)- methyl]- benzo[b]thiophene-2-carboxylic acid (2-amino-phenyl)- ¹H NMR: (DMSO) δ (ppm): 9.88 (s,1H), 8.25 (s, 1H), 7.97 (d, J=8.5, 1H), 7.91 (s, 1H), 7.49 (d, J=8.5,1H), 7.16 (d, J=7.5, 1H), 6.98 (t, J=7.25, 1H), 6.78 (d, J=8.0, 1H),6.65 (d, J=8.0, 1H), 6.60 (t, J=7.5, 1H), 6.35 (s, 1H), 6.05 # (d,J=9.0, 1H), 5.96 (s, 1H), 4.97 (s, 2H), 4.36 (d, J=5.0, 2H), 3.65 (s,3H), 3.58 (s, 3H). MS: (calc.) 433.1; (obt.) 434.5 (MH)⁺. 171 307

5-[(6-Methoxy- benzothiazol-2- ylamino)-methyl]benzofuran-2- carboxylicacid (2- amino-phenyl)- amide MS: (calc.) 444.1; (obt.) 445.4 (MH)⁺. 172308

5-[(3,4,5- Trimethoxy- phenylamino)- methyl]-benzofuran- 2-carboxylicacid (2-amino-phenyl)- amide ¹H NMR: (DMSO) δ (ppm): 9.82 (s, 1H), 7.75(s, 1H); 7.67 (s, 1H); 7.63 (d, J=8.6 Hz, 1H); 7.47 (dd, J=8.6, 1.6 Hz,1H); 7.16 (dd, J=7.8, 1.4, Hz, 1H); 6.96 (dt, J=8.0, 1.6 Hz, 1H); 6.76(dd, J=8.0, 1.4 Hz, 1H); 6.58 (dt, J=7.6, 1.4 Hz, 1H); 6.11 # (t, J=6.1Hz, 1H); 5.90 (s, 2H); 4.95 (s, 2H); 4.34 (d, J=5.9 Hz, 2H); 3.63 (s,6H); 3.49 (s, 3H). MS: (calc.) 447.2; (obt.) 448.5 (MH)⁺. 173 309

5-[4-(4-Methoxy- phenyl)-pyrimidin- 2-ylsulfanylmethyl]- benzofuran-2-carboxylic acid (2- amino-phenyl)- amide ¹H NMR: (DMSO) δ (ppm): 9.85(s, 1H), 8.63 (d, J=5.3 Hz, 1H), 8.19 (dd, J=6.8, 2.0 Hz, 2H); 7.89 (d,J=1.0 Hz, 1H); 7.73 (d, J=5.5 Hz, 1H); 7.66 (m, 2H); 7.59 (dd, J=8.6,1.8 Hz, 1H); 7.17 (dd, J=7.6, 1.2 Hz, 1H); 7.10 # (dd, J=6.8, 2.0 Hz,2H); 6.98 (dt, J=8.0, 1.8 Hz, 1H); 6.78 (dd, J=7.8, 1.2 Hz, 1H); 6.59(ddd, J=1.4, 7.6, 8.8 Hz, 1H); 4.97 (s, 2H); 4.64 (s, 2H); 3.86 (s, 3H).MS: (calc.) 482.5; (obt.) 483.5 (MH)⁺. 174 310

2-(3,4-Dimethoxy- benzylamino)- benzothiazole-6- carboxylic acid (2-amino-phenyl)- amide ¹H NMR: (DMSO) δ (ppm): 948 (s, 1H), 8.00 (d,J=2.0, 1H), 7.77 (dd, J=8.2, 1.6, 1H), 7.11 (d, J=6.7, 1H), 7.06-7.04(m, 2H), 6.92 (dt, J=7.6, 1.6 Hz, 1H), 6.86-6.84 (m, 1H), 6.79 (d, J=8.2Hz, 1H), 6.73 (dd, J=8.2, 1.6 Hz, 6.55 (dt, J=7.6, # 1.2 Hz, 1H), 5.11(s, 2H), 4.86 (brs, 2H), 3.71 (s, 3H), 3.69 (s, 3H). MS: (calc.) 434;(obt.) 435.4 (MH)⁺. 175 311

2-(3,4,5- Trimethoxy- benzylamino)- benzothiazole-6- carboxylic acid (2-amino-phenyl)- amide ¹H NMR: (DMSO) δ (ppm): 9.54 (s, 1H), 8.70 (brt,J=5.48, 1H), 8.30 (d, J=1.76, 1H), 7.86 (dd, J=8.32, 1.67, 1H), 7.45 (d,J=8.41, 1H), 7.15 (d, J=6.85, 1H), 6.94 (m, 1H), 6.76 (dd, J=7.93, 1.27,1H), 6.72 (s, 2H), 6.58 (m, 1H), 4.89 (brs, 2H), 4.55 # (d, J=5.48, 2H),3.76 (s, 6H), 3.63 (s, 3H). MS: (calc.) 464; (obt.) 465.5 (MH)⁺. 176 312

2-[(Pyridin-3- ylmethyl)-amino]- benzothiazole-6- carboxylic acid (2-amino-phenyl)- amide ¹H NMR: (DMSO) δ (ppm): 9.56 (s, 1H), 8.83 (t,J=5.9 Hz, 1H); 8.62 (d, J=1.4 Hz, 1H); 8.49 (dd, J=1.6, 4.7 Hz, 1H);8.32 (d, J=1.8 Hz, 1H); 7.88 (dd, J=1.9, 6.4 Hz, 1H); 7.81 (m, 1H); 7.40(m, 1H); 7.46 (d, J=8.4 Hz, 1H); 7.16 (d, J=6.4 Hz, # 1H); 6.96 (dt,J=1.0, 8.6 Hz, 1H); 6.77 (dd, J=1.2, 7.8 Hz, 1H); 6.60 (dt, J=1.0, 8.8Hz, 1H); 4.90 (s, 2H); 4.68 (d, J=5.7 Hz, 2H). MS: (calc.) 375.1; (obt.)376.4 (MH)⁺. 177 313

1-(3,4-Dimethoxy- benzyl)-2,3- dihydro-1H-indole- 5-carboxylic acid(2-amino-phenyl)- amide ¹H NMR: (DMSO) δ (ppm): 9.29 (s, 1H), 7.71 (dd,J=8.22, 1.77, 1H), 7.66 (brm, 1H), 7.12 (dd, J=7.93, 1.47, 1H),6.93-6.89 (m, 3H), 6.84 (dd, J=8.22, 1.96, 1H), 6.75 (dd, J=8.02, 1.37,1H), 6.65 (d, J=8.41, 1H), 6 57 (dt, J=7.53, 1.30, 1H), 4.82 (s, # 2H),3.73 (s, 6H), 3.41 (t, J=8.51, 2H), 2.98 (t, J=8.51, 2H). MS: (calc.)403; (obt.) 404.5 (MH)⁺.

Example 178N-(2-Amino-phenyl)-4-{[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-methyl}-benzamide(314)

Title compound was obtained according to the scheme 6 similarly to thecompound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone asthe starting material 1-(2,4-dimethyl-thiazol-5-yl)-ethanone (Table 11).Characterization of the title compound is provided in the Table 12.TABLE 11 Heteroarylmethyl ketones used in the synthesis of examples178-188 Structure of Example of the Heteroary lmethyl Name of the finalproduct it Cmpd ketone Heteroary lmethyl ketone Scheme was used for

1-(2,4-Dimethyl-thiazol-5- yl)-ethanone 178

1-(2H-Pyrazol-3-yl)- ethanone 179

1-(2,4-Dimethyl-oxazol-5- yl)-ethanone 180 320

1-(3-Hydroxymethyl- isoxazol-5-yl)-ethanone 59 181 324

1-(3-(Hydroxymethyl)-5- methylisoxazol-4- yl)ethanone 60 182 327

1-(3H-1,2,3-Triazol-4- yl)ethanone 61 183, 184 333

1-(2-Methylimidazo[1,2- a]pyridin-3-yl)ethanone 62 185

1 -(2-Amino-4- methylthiazol-5- yl)ethanone 186, 187

Example 179N-(2-Amino-phenyl)-4-{[4-(2H-pyrazol-3-yl)-pyrimidin-2-ylamino]-methyl}-benzamide(315)

Title compound was obtained according to the scheme 6 similarly to thecompound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone asthe starting material 1-(2H-pyrazol-3-yl)-ethanone (Table 11).Characterization of the title compound is provided in the Table 12.

Example 180N-(2-Amino-phenyl)-4-{[4-(2,4-dimethyl-oxazol-5-yl)-pyrimidin-2-ylamino]-methyl}-benzamide(316)

Title compound was obtained according to the scheme 6 similarly to thecompound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone asthe starting material 1-(2,4-dimethyl-oxazol-5-yl)-ethanone (Table 11).Characterization of the title compound is provided in the Table 12.

Example 181N-(2-Amino-phenyl)-4-{[4-(2,4-dimethyl-oxazol-5-yl)-pyrimidin-2-ylamino]-methyl}-benzamide(317)

Step 1. Ethyl 5-(2-methyl-1,3-dioxolan-2-yl)isoxazole-3-carboxylate(318)

A reaction mixture consisting of ethyl 5-acetylisoxazole-3-carboxylate(2.53 g, 13.8 mmol), ethylene glycol (1.29 g, 20.7 mmol) and p-TsOH(0.13 g, 0.69 mmol) in benzene (50 mL) was refluxed with the Dean-Starkadapter for 24 hours (scheme 59). Most of the solvent was removed underreduced pressure and the residue was partitioned between saturatedNaHCO₃ and EtOAc. Organic layer was collected, washed with brine, water,and dried over MgSO₄. Evaporation of the dried extract under reducedpressure afforded the title compound as an oil (3.14 g, 100% yield),which was used for next step without further purification. ¹H NMR(DMSO-d₆) δ (ppm): 6.89 (s, 1H), 4.35 (q, J=7.2 Hz, 2H), 4.07-4.01 (m,2H), 4.01-3.94 (m, 2H), 1.70 (s, 3H), 1.32 (t, J=7.0 Hz, 3H). MS (m/z):227.21 (calc) 228.1 (MH⁺) (found).

Step 2. (5-(2-Methyl-1,3-dioxolan-2-yl)isoxazol-3-yl)methanol (319)

To a solution of the dioxolane 318 (3.14 g, 13.8 mmol) in a 1:2 mixtureof EtOH-THF (45 mL) NaBH₄ (0.68 g, 18.0 mmol) was added. The reactionmixture was stirred at room temperature for 2 hours, treated with waterand the organic solvents were evaporated. The aqueous phase wasextracted with EtOAc and combined organic layers were successivelywashed with H₂O and brine, dried over MgSO₄ and concentrated underreduced pressure to afford the title compound as oil (2.39 g, 93% yield)which was used for next step without further purification. ¹H NMR(DMSO-d₆) δ (ppm): 6.43 (s, 1H), 5.47 (t, J=5.9 Hz, 1H), 4.47 (d, J=5.9Hz, 2H), 4.06-4.02 (m, 2H), 3.94-3.90 (m, 2H), 1.66 (s, 3H). MS (m/z):185.18 (calc) 186.1 (MH+) (found).

Step 3. 1-(3-(Hydroxymethyl)isoxazol-5-yl)ethanone (320)

To a solution of the carbinol 319 (2.39 g, 12.9 mmol) in MeOH (30 mL)10% HCl (30 mL) was added. The reaction mixture was stirred at 70° C.for 18 hours, cooled and neutralized to pH 6 using 1M NaOH solution.MeOH was evaporated and the resulting aqueous phase was extracted withEtOAc. The organic layer was washed with brine, dried under MgSO₄ andconcentrated under reduced pressure to produce the title compound as abeige solid (1.67 g, 92% yield), which was used for next step withoutfurther purification. ¹H NMR (DMSO-d₆) δ (ppm): 7.25 (s, 1H), 5.62 (t,J=6.1 Hz, 1H), 4.56 (d, J=5.9 Hz, 2H), 2.56 (s, 3H). MS (m/z): 141.12(calc) 142.1 (MH+) (found)

Step 4.N-(2-Amino-phenyl)-4-{[4-(2,4-dimethyl-oxazol-5-yl)-pyrimidin-2-ylamino]-methyl}-benzamide(317)

Title compound was obtained according to the scheme 6 similarly to thecompound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone asthe starting material the ketone 320 (Table 11). Structure andcharacterization of the title compound are presented in the Table 12.

Example 182N-(2-aminophenyl)-4-((4-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyrimidin-2-ylamino)methyl)benzamide(321)

Step 1. Methyl5-methyl-4-(2-methyl-1,3-dioxolan-2-yl)-isoxazole-3-carboxylate (322)

Title compound was obtained similarly to the dioxolane 318 in 82% yieldaccording to the scheme 60. MS (m/z): 227.21 (calc) 228.1 (MH+) (found)

Step 2. (5-Methyl-4-(2-methyl-1,3-dioxolan-2-yl)isoxazol-3-yl)methanol(323)

Title compound was obtained similarly to the carbinol 319 in 94% yieldaccording to the scheme 60. ¹H NMR (DMSO-d₆) δ(ppm): 5.21 (t, J=5.7 Hz,1H), 4.48 (d, J=5.7 Hz, 2H), 3.98-3.94 (m, 2H), 3.71-3.67 (m, 2H), 2.39(s, 3H), 1.60 (s, 3H). MS (m/z): 199.20 (calc) 200.1 (MH+) (found)

Step 3. 1-(3-(Hydroxymethyl)-5-methylisoxazol-4-yl)ethanone (324)

Title compound was obtained similarly to the ketone 320 in 77% yieldaccording to the scheme 60. ¹H NMR (DMSO-d₆) δ (ppm): 5.45 (t, J=5.9 Hz,1H), 4.66 (d, J=5.9 Hz, 2H), 2.66 (s, 3H), 2.51 (s, 3H). MS (m/z):155.15 (calc) 156.1 (MH+) (found)

Step 4.N-(2-aminophenyl)-4-((4-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyrimidin-2-ylamino)methyl)benzamide(317)

Title compound was obtained according to the scheme 6 similarly to thecompound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone asthe starting material the ketone 324 (Table 11). Characterization of thetitle compound is provided in the Table 12.

Examples 183, 184N-(2-aminophenyl)-4-((4-(1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-2-ylamino)methyl)benzamide(325) andN-(2-aminophenyl)-4-((4-(3-methyl-3H-1,2,3-triazol-4-yl)pyrimidin-2-ylamino)methyl)benzamide(326)

Step 1. 1-(3H-1,2,3-Triazol-4-yl)ethanone (327)

To a solution of 3-butyn-2-one (627 mg, 9.21 mmol) in xylene (10 mL) wasadded azidotributyltin (4.00 g, 12.0 mmol). The reaction mixture wasstirred at 140° C. for 3 hours in a sealed flask. Xylene was evaporatedand the residue was purified by flash chromatography, eluent EtOAc toafford the title compound (645 mg, 63% yield). ¹H NMR (DMSO-d₆) δ(ppm):8.51 (s, 1H), 2.56 (s, 3H). MS (m/z): 111.10 (calc) 112.1 (MH⁺) (found)

Step 2.(E)-3-(dimethylamino)-1-(1-methyl-1H-1,2,3-triazol-4-yl)prop-2-en-1-one(328) and(E)-3-(dimethylamino)-1-(3-methyl-3H-1,2,3-triazol-4-yl)prop-2-en-1-one(329)

Mixture of title compounds 328 and 329 was obtained in 24% yieldaccording to the scheme 6 similarly to the compound 23a (Example 29,step 1) using instead of 1-pyrazin-2-yl-ethanone as the startingmaterial ketone 327 (Table 11). MS (m/z): 180.21 (calc) 181.1 (MH⁺)(found).

¹H NMR (DMSO-d₆) δ (ppm) (328, major isomer, tentative assignment): 8.01(s, 1H), 7.74 (d, J=12.3 Hz, 1H), 5.73 (d, J=12.3 Hz, 1H), 4.18 (s, 3H),3.15 (s, 3H), 2.88 (s, 3H).

¹H NMR (DMSO-d₆) δ (ppm) (329, minor isomer, tentative assignment): 8.26(s, 1H), 7.71 (d, J=10.8 Hz, 1H), 5.66 (d, J=12.1 Hz, 1H), 4.19 (s, 3H),3.16 (s, 3H), 2.92 (s, 3H).

Step 3.4-((4-(1-Methyl-1H-1,2,3-triazol-4-yl)pyrimidin-2-ylamino)methyl)benzoicacid (330) and4-((4-(3-methyl-3H-1,2,3-triazol-4-yl)pyrimidin-2-ylamino)methyl)benzoicacid (331)

Mixture of title compounds was obtained in 80% yield according to thescheme 6 similarly to the compound 25a (Example 29, step 3) usinginstead of enamino ketone 23a as a starting material mixture of enaminoketones 328 and 329. ¹H NMR (DMSO-d₆) δ (ppm) (328, major isomer,tentative assignment): 12.80 (s, 1H), 8.33 (d, J=5.1 Hz, 1H), 8.17 (s,1H), 7.94 (t, J=6.5 Hz, 1H), 7.85 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.2 Hz,2H), 7.02 (d, J=4.7 Hz, 1H), 4.60 (d, J=6.5 Hz, 2H), 4.22 (s, 3H). MS(m/z): 310.31 (calc) 311.2 (MH+) (found)

Step 4.N-(2-aminophenyl)-4-((4-(1-methyl-1H-1,2,3-triazol-4-yl)pyrimidin-2-ylamino)methyl)benzamide(325) andN-(2-aminophenyl)-4-((4-(3-methyl-3H-1,2,3-triazol-4-yl)pyrimidin-2-ylamino)methyl)benzamide(326)

Title compounds were obtained in 53 and 7% yields according to thescheme 6 similarly to the compound 26a (Example 29, step 4) usinginstead of acid 25a as a starting material mixture of acids 330 and 331.Characterization of the title compounds is provided in the Table 12.

Example 185N-(2-Aminophenyl)-4-((4-(2-methylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide(332)

Step 1. 1-(2-Methylimidazo[1,2-a]pyridin-3-yl)ethanone (333)

1,1′-Azobis(cyclohexanecarbonitrile) (catalytic amount) was added to asolution of pentane-2,4-dione (1.00 g, 9.99 mmol) and N-bromosuccinimide(1.96 g, 10.99 mmol) in CHCl₃ (20 mL). The reaction mixture was stirredfor 1 hour, filtered and the filtrate was concentrated under reducedpressure. The residue was re-dissolved in a 1:1 mixture of THF/Et₂O (20mL), then pyridin-2-amine (723 mg, 7.68 mmol) was added and the reactionmixture was refluxed overnight. After cooling the solvent was removedunder reduced pressure and the residue was purified by columnchromatography, eluents EtOAc, then EtOAc-MeOH (96:4), to afford thetitle compound (475 mg 35% yield). ¹H NMR (DMSO-d₆) δ (ppm): 9.59 (dt,J=6.8, 1.4 Hz, 1H), 7.68 (dt, J=8.8, 1.2 Hz, 1H), 7.56 (ddd, J=8.8, 6.8,1.4 Hz, 1H), 7.17 (td, J=6.8, 1.4 Hz, 1H), 2.72 (s, 3H), 2.58 (s, 3H).MS (m/z): 174.20 (calc) 175.1 (MH⁺) (found).

-   [M. Anderson, J. F. Beattie, et. al. Bioorg. Med. Chem. Lett.; 2003,    13; 3021-3026].

Step 2.N-(2-Aminophenyl)-4-((4-(2-methylimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide(332)

Title compound was obtained according to the scheme 6 similarly to thecompound 26a (Example 29) using instead of 1-pyrazin-2-yl-ethanone asthe starting material the ketone 333 (Table 11). Characterization of thetitle compound is provided in the Table 12.

Examples 186 and 1874-((4-(2-Amino-4-methylthiazol-5-yl)pyrimidin-2-ylamino)methyl)-N-(2-aminophenyl)benzamide(334) andN-(2-aminophenyl)-4-((4-(5-(2-(dimethylamino)acetamido)-3-methylthiophen-2-yl)pyrimidin-2-ylamino)methyl)benzamide(335)

Step 1. 2-(bis-Boc-Amino-)-5-acetyl-4-methylthiazole (336)

Pyridine (1.11 g, 14.1 mmol) was added to a solution of Boc₂O (3.07 g,14.1 mmol) and 1-(2-amino-4-methylthiazol-5-yl) (2.00 g, 12.8 mmol) inDCM (20 mL). The reaction mixture was stirred for 3 days at roomtemperature. The same amount of Boc₂O was added and the reaction mixturewas stirred for another 3 days. DCM was evaporated under reducedpressure, water was added and the resultant mixture was extracted withEtOAc. The organic layer was washed with brine, dried over MgSO₄ andconcentrated under reduced pressure to afford the title compound asorange oil (4.6 g, 100% yield). ¹H NMR (DMSO-d₆) δ (ppm): 2.54 (s, 3H),2.49 (s, 3H), 1.53 (s, 18H). MS (m/z): 356.44 (calc) 357.1 (MH+) (found)

Step 2.(E)-1-[2-(bis-Boc-Amino-)-4-methylthiazol-5-yl]-3-(dimethylamino)prop-2-en-1-one(337)

Following the procedure described for the synthesis of enamino ketone23a (scheme 6) but substituting 1-(pyrazin-2-yl)-ethanone for the ketone336, title compound was obtained in 16% yield. ¹H NMR (DMSO-d₆) δ (ppm):7.65 (d, J=12.1 Hz, 1H), 5.34 (d, J=12.1 Hz, 1H), 3.14 (s, 3H), 2.87 (s,3H), 2.50 (s, 3H), 1.51 (s, 18H). MS (m/z): 411.52 (calc) 412.3 (MH⁺)(found).

Step 3.(E)-1-[2-(Boc-Amino-)-4-methylthiazol-5-yl]-3-(dimethylamino)prop-2-en-1-one(338)

A solution of enamino ketone 337 (859 mg, 2.09 mmol) in methanol (12 mL)was treated with NaOMe solution (25% ww, 1.9 ml). The reaction mixturerefluxed for 24 hours, treated with NaOH solution (1M, 3 ml), cooled tothe room temperature, carefully neutralized (pH 7.5-8) with 1M HCl andextracted with EtOAc. Extract was dried over MgSO₄, filtered andevaporated to provide a residue corresponding to the title compound (721mg, more than quantitative yield), which was used for the next stepwithout further purification. MS (m/z): 311.40 (calc) 312.1 (MH+)(found).

Step 4.4-((4-(2-(tert-Butoxycarbonylamino)-4-methylthiazol-5-yl)pyrimidin-2-ylamino)methyl)benzoicacid (339)

Following the procedure described for the synthesis of the acid 25a(scheme 6, step 3) but substituting enamino ketone 23a for the enaminoketone 338, title compound was obtained in 18% yield and was used forthe next steps without further purification. MS (m/z): 441.50 (calc)442.3 (MH+) (found).

Steps 5 and 6.4-((4-(2-Amino-4-methylthiazol-5-yl)pyrimidin-2-ylamino)methyl)-N-(2-aminophenyl)benzamide(334)

Title compound was obtained according to the procedure described for thesynthesis of compound 26a (scheme 6, step 4, coupling with 1,2-phenylenediamine) followed by the procedure described for the synthesis of thecompound 117 (scheme 28, step 5, amino-group deprotection). Yield 78%over two steps. Characterization of the title compound is provided inthe Table 12.

Step 7.4-((4-(2-Amino-4-methylthiazol-5-yl)pyrimidin-2-ylamino)methyl)benzoicacid (340)

Title compound was obtained according to procedure described for thesynthesis of the compound 117 (scheme 28, step 5, amino-groupdeprotection) in a quantitative yield (purity ca 90%). MS (m/z): 341.39(calc) 342.1 (MH+) (found).

Step 8.4-((4-(2-((Dimethylamino)methylcarbamoyl)-4-methylthiazol-5-yl)pyrimidin-2-ylamino)methyl)benzoicacid (341)

Dimethylamino acetyl chloride hydrochloride (59.0 mg, 0.37 mmol) wasadded to a solution of the acid 340 (98.1 mg, 0.29 mmol) in pyridine (5mL). The reaction mixture was stirred at room temperature for 1 day thenanother portion of dimethylaminoacetyl chloride hydrochloride (40 mg,0.12 mmol) was added and the mixture was stirred at 40° C. for anotherday. Pyridine was evaporated under reduced pressure and MeOH was added.A solid material was formed which was collected by filtration andpurified by preparative RP HPLC (column AQUASIL C-18; 5 μM; 230×21.2 mm;eluent 20-80% MeOH in water) to afford 24,5 mg of the title compound(20% yield). MS (m/z): 426.49 (calc) 427.2 (MH⁺) (found).

Step 9.N-(2-aminophenyl)-4-((4-(5-(2-(dimethylamino)acetamido)-3-methylthiophen-2-yl)pyrimidin-2-ylamino)methyl)benzamide(335)

Title compound was obtained according to the procedure described for thesynthesis of compound 26a (scheme 6, step 4) in 15% yield (purified bypreparative HPLC, column AQUASIL C-18; 5 μM; 230×21.2 mm; eluent 20-80%MeOH in water). Characterization of the title compound is provided inthe Table 12.

Example 1884-(4-(Pyridin-3-yl)pyrimidin-2-ylamino)-N-(2-aminophenyl)benzamide (342)Step 1. 4-(4-(Pyridin-3-yl)pyrimidin-2-ylamino)benzoic acid (343)

Title compound was prepared according to the procedure described for thesynthesis of compound 25a (scheme 6, step 3) replacing the guanindine 24by 4-guanidinobenzoic acid (344) (Zlatoidsky P., Maliar T. Eur. J. Med.Chem Chim. Ther.; 1996, 31, 895-900) and(E)-3-(dimethylamino)-1-(pyrazin-2-yl)-prop-2-en-1-one (23a) by(E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (345) (ZimmermannJ., Buchdunger E., et al. Bioorg. Med. Chem. Lett., 1996, 6, 1221-1226).Yield of the product 28%. MS (m/z): 292.29 (calc) 293.1 (MH+) (found).

Step 2.4-(4-(Pyridin-3-yl)pyrimidin-2-ylamino)-N-(2-aminophenyl)benzamide (342)

Title compound was obtained in 54% yield according to the proceduredescribed for the synthesis of compound 26a (scheme 6, step 4) replacingacid 25a by the acid 343. Characterization of the title compound isprovided in the Table 12.

Example 189N-(2-Amino-phenyl)-4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzamide(346) Step 1. 4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzoic acid(347)

A solution of 4-formyl-benzoic acid (1.0 g, 6.7 mmol),thiazolidine-2,4-dione (0.78 g, 6.7 mmol) and piperidine (1.32 ml, 13.3mmol) in 2-methoxy-ethanol (20 ml) was refluxed for 2 hrs, cooled to theroom temperature, evaporated and the oily residue was re-dissolved inwater. Acidification of this solution with conc. HCl (pH 1-2) produced aprecipitate which was collected by filtration, dried and triturated withhot acetone to afford the title compound (1.06 g, 64% yield). LRMS:249.2 (calcd.), 248.1 [M−H]⁻ (found).

Step 2.{2-[4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzoylamino]-phenyl}-carbamicacid tert-butyl ester (348)

Following the procedure described for the synthesis of compound 115(scheme 28) but substituting the acid 114 by the acid 347, titlecompound was obtained in 63% yield. LRMS: 439.5 (calcd.), 462.4 [M+Na]⁺(found).

Step 3.N-(2-Amino-phenyl)-4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-benzamide(346)

Following the procedure described for the synthesis of compound 117(scheme 28) but substituting the amide 116 by the amide 348, titlecompound was obtained in 37% yield. ¹H NMR: (400 MHz, DMSO-d₆, δ (Ppm):9.72 (s, 1H), 8.06 (d, j=8.2 Hz, 2H), 7.79 (s, 1H), 7.69 (d, J=8.4, 2H),7.14 (d (dd) J=7.8, 1H), 6.95 (d (dd), J=1.6 Hz, J=9.0, 1H), 6.75 (dd,J=1.2 Hz, J=8.0 Hz, 1H), 6.56 (t (dd), J=7.2 Hz 1H). LRMS: 339.4(calcd.), 340.4 [MH]⁺ (found).

Example 190N-(2-Amino-phenyl)-4-(2,4-dioxo-thiazolidin-5-ylmethyl)-benzamide (349)Step 1. 4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-benzoic acid methylester (350)

A solution of 4-formyl-benzoic acid methyl ester (1.0 g, 6.7 mmol),thiazolidine-2,4-dione (0.78 g, 6.7 mmol) and piperidine (0.66 ml, 6.7mmol) in 2-methoxy-ethanol (20 ml) was refluxed for 2 hrs, cooled to theroom temperature and evaporated. The residue was triturated with CH₂Cl₂to produce a crystalline material which was collected by filtration toafford the title compound (620 mg, 35% yield). LRMS: 263.3 (calcd.),264.1 [MH]⁺ (found).

Step 2. 4-(2,4-Dioxo-thiazolidin-5-ylmethyl)-benzoic acid methyl ester(351)

A solution of the methyl ester 350 (615 mg, 2.32 mmol) in MeOH (120 ml)was hydrogenated over 10% Pd/C (615 mg, Degussa type) for 2 hours atroom temperature. Another portion of Pd/C (300 mg) was added and thehydrogenation proceeded for another 3 hrs (monitored by MS). Thereaction mixture was filtered through a celite pad, evaporated and theresidue was purified by flash chromatography, eluent EtOAc—CH₂Cl₂ (1:2),to produce the title compound (570 mg, 92% yield). LRMS: 265.3 (calcd.),266.1 [MH]⁺ (found).

Step 3. 4-(2,4-Dioxo-thiazolidin-5-ylmethyl)-benzoic acid (352)

A solution of methyl ester 351 (250 mg, 0.94 mmol) in AcOH (10 ml) wastreated with conc. HCl (5 ml) and the reaction mixture was heated at120° C. for 2 hrs, cooled and evaporated to produce a solid residuewhich was re-suspended in water and collected by filtration to affordthe title compound (98 mg, 41% yield). LRMS: 251.3 (calcd.), 250.1[M−H]⁻ (found).

Step 4.N-(2-Amino-phenyl)-4-(2,4-dioxo-thiazolidin-5-ylmethyl)-benzamide (349)

Following the procedure described for the synthesis of compound 10a(scheme 2, Example 2) but replacing acid 9 by the acid 352, titlecompound was obtained in 51% yield. ¹H NMR: (400 MHz, DMSO-d₆, δ (ppm):12.04 (br s, 1H), 9.62 (s, 1H), 7.90 (d, j=8.2 Hz, 2H), 7.36 (d, J=8.2,2H), 7.16 (d (dd) J=8.4, 1H), 7.13 (d (dd), J=6.7, 1H), 6.95 (dd, J=1.6Hz, J=7.8 Hz, 1H), 6.75 (dd, j=1.4 Hz, j=8.0 Hz, 1H), 6.57 (dd, j=1.4Hz, 7.6 Hz, 1H), 4.99 (dd, J=4.7 Hz, J=9.0 Hz, 1H), 4.96 (br s, 2H),3.45 (dd, J=4.5 Hz, J=14.1 Hz, 1H), 3.22 (dd, J=9.0 Hz, J=14.3 Hz, 1H).LRMS: 341.3 (calcd.), 342.3 [MH]⁺ (found).

Example 191(E)-N-(2-aminophenyl)-4-(2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)ethoxy)benzamide(353) Step 1: 4-(2-bromoethoxy)benzaldehyde (354)

To a suspension of K₂CO₃ (4.52 g, 32.7 mmol), 1,2-dibromoethane (10.6ml, 122.8 mmol) in DMF (12 mL) was added a solution of4-hydroxybenzaldehyde (1.0 g, 8.2 mmol) in DMF (3 mL) at 0° C. Themixture was stirred at room temperature for 18 h., filtered andevaporated. The residue was purified by silica gel column chromatographywith gradient of EtOAc-hexane (increasing percentage of EtOAc from 20 to25%) to afford the title compound (1.21 g, 64% yield). ¹H NMR: (CDCl₃) δ(ppm): 9.88 (s, 1H), 7.84 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H),4.38 (t, J=6 Hz, 2H), 3.67 (t, J=6 Hz, 2H). LRMS (ESI): (calc.) 227.9,229.9; (found) 229.1, 231.3 (MH)⁺.

Step 2: Methyl 4-(2-(4-formylphenoxy)ethoxy)benzoate (355)

To a solution of 354 (1.21 g, 5.27 mmol) in DMF (10 mL) was added methyl4-hydroxybenzoate (0.80 g, 5.27 mmol) and K₂CO₃ (2.91 g, 21.1 mmol). Theresultant mixture was stirred at 60° C. for 6 h, filtered, andevaporated. The residue was purified by silica gel columnchromatography, eluent EtOAc-hexane (1:2) to afford title compound (0.83g, 53%). LRMS (ESI): (calc.) 300.3; (found) 301.4 (MH)⁺.

Step 3: (E)-Methyl4-(2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)ethoxy)benzoate(356)

To a solution of 355 (1.59 g, 3.86 mmol) in toluene (10 mL) was addedthiazolidine-2,4-dione (542 mg, 4.63 mmol), benzoic acid (61.3 mg, 0.50mmol) and piperidine (57 uL, 0.58 mmol). The resultant mixture wasrefluxed with the Dean-Stark adapter for ½ h and cooled to the roomtemperature. A precipitate formed which was collected by filtration toafford the title compound (1.41 g, 92%). ¹H NMR: (DMSO-d₆) δ (ppm): 7.90(d, J=8.8 Hz, 2H), 7.73 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.14 (d, J=8.8Hz, 2H), 7.08 (d J=8.8 Hz, 2H), 4.42 (bs, 4H), 3.80 (s, 3H). LRMS (ESI):(calc.) 399.1; (found) 400.0 (MH)⁺.

Step 4:(E)-4-(2-(4-((2,4-Dioxothiazolidin-5-ylidene)methyl)phenoxy)ethoxy)benzoicacid (compound 357)

To a solution of methyl ester 356 (647 mg, 1.62 mmol) in THF (15 mL) wasadded methanol (2 mL), water (2 mL) and lithium hydroxide monohydrate(340 mg, 8.11 mmol). The mixture was heated at 60° C. for 1 hour,acidified with 10% HCl solution and extracted with ethyl acetate. Theorganic extract was dried over MgSO₄, filtered, and evaporated to affordthe title compound (141 mg, 22%). ¹H NMR: (MeOD-d₄) δ (ppm): 7.97 (d,J=8.8 Hz, 2H), 7.75 (s, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.8 Hz,2H), 7.04 (d, J=8.8 Hz, 2H), 4.44 (4H, bs). LRMS (ESI): (calc.) 385.4;(found) 392.3 (MLi)⁺.

Step 5:(E)-N-(2-Aminophenyl)-4-(2-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenoxy)ethoxy)benzamide(353)

Acid 357 (141 mg, 0.37 mmol), benzene-1,2-diamine (40 mg, 0.37 mmol) andBOP (161 mg, 0.37 mmol) were dissolved in CH₃CN (5 mL). Triethylamine(0.73 mmol, 203 μL) was added and the reaction was stirred for 18 hoursat room temperature. The solvents were removed under reduced pressureand the residue was purified by silica gel column chromatography withgradient elution by EtOAc-hexane mixture (increasing percentage of EtOAcfrom 33 to 100%) to afford the title compound (34.2 mg, 19%). ¹H NMR:(DMSO-d₆) δ (ppm): 10.00 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 7.57-7.65(m, 3H), 7.49 (t, J=7.6 Hz, 2H), 7.36-7.43 (m, 2H), 7.31-7.35 (m, 1H),4.59 (s, 2H), 4.23 (s, 2H), 3.74 (s, 3H), 3.11-3.20 (m, 2H), 2.37 (t,J=7.2 Hz, 2H), 1.60-1.71 (m, 2H), 1.45-1.55 (m, 2H), 1.32-1.43 (m, 2H).LRMS (ESI): (calc.) 460.5; (found) 461.3 (MH)⁺.

Example 192N-(2-Aminophenyl)-4-(2-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)ethoxy)benzamide(358) Step 1: Methyl4-(2-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)ethoxy)benzoate (359)

To a solution of 356 (scheme 67) (672 mg, 1.68 mmol) in 1,4-dioxane (10mL) was added 10% Pd/C (2.3 g, 2.18 mmol). The resultant mixture wasstirred under hydrogen atmosphere for 2 days at room temperature,filtered through a celite pad and concentrated under reduced pressure toafford 359 (379 mg, 56%). LRMS (ESI): (calc.) 401.4; (found) 424.2(M+Na)⁺. ¹H NMR: (CDCl₃) δ (ppm): 8.15 (bs, 1H), 7.99 (d, J=8.8 Hz, 2H),7.16 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H),4.52 (dd, J=9.2, 4.0 Hz, 1H), 4.38-4.37 (m, 2H), 4.32-4.32 (m, 2H), 3.89(s, 3H), 3.45 (dd, J=14.1, 4.0 Hz, 1H), 3.14 (dd, J=14.0, 9.2 Hz, 1H).

Step 2:4-(2-(4-((2,4-Dioxothiazolidin-5-yl)methyl)phenoxy)ethoxy)benzoic acid(360)

To a solution of methyl ester 359 (872 mg, 2.17 mmol) in glacial AcOH(30 mL) was added conc. HCl (10 mL). The mixture was heated at 120° C.for 3 hours. The solvents were remove under reduced pressure to affordthe title compound (833 mg, 99%). ¹H NMR: (DMSO-d₆) δ (ppm): 12.61 (bs,1H), 12.01 (s, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.08(d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.91 (dd, J=9.2, 4.4 Hz, 1H),4.40-4.42 (m, 2H), 4.33-4.36 (m, 2H), 3.32 (d, J=4.0 Hz, 1H), 3.10 (dd,J=14.0, 9.6 Hz, 1H). LRMS (ESI): (calc.) 387.4; (found) 386.2 (M−H)⁻.

Step 3:N-(2-aminophenyl)-4-(2-(4-((2,4-dioxothiazolidin-5-yl)methyl)phenoxy)ethoxy)benzamide(358)

Following the same procedure as described for compound 393 (step 5,scheme 67, example 191) but substituting acid 357 for the acid 360 titlecompound was obtained as a beige solid (57 mg, 33% yield). ¹H NMR:(DMSO-d₆) δ (ppm): 9.34 (s, 1H), 7.74-7.78 (m, 3H), 6.93-6.98 (m, 3H),6.88 (d J=8.8 Hz, 2H), 6.73-6.78 (m, 3H), 6.57 (dd, J=8.0, 1.2 Hz, 1H),6.38 (dt, J=8.0, 1.2 Hz, 1H), 4.68 (dd, J=8.8, 4.4 Hz, 2H), 4.19-4.21(m, 2H), 3.11 (d, J=4.4 Hz, 1H), 2.88 (dd, J=14.0, 9.2 Hz, 1H). LRMS(ESI): (calc.) 477.4; (found) 478.4 (MH)⁺.

TABLE 12 Characterization of examples 178-188. Ex Cpd Structure NameCharacterization Scheme 178 314

N-(2-amino- phenyl)-4- ((4-(2,4- dimethyl thiazol-5- yl)pyrimidin-2-ylamino)methyl)benzamide ¹H NMR (DMSO-d₆) δ(ppm): 9.56 (s, 1H), 8.30 (d,J=5.1 Hz, 1H), 7.92 (s, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.43 (d, J=7.4 Hz,2H), 7.12 (d, J=7.6 Hz, 1H), 6.94 (td, J=7.8, 1.4 Hz, 1H), 6.82 (d,j=5.1 Hz, 1H), 6.75 (dd, J=8.0, 1.4 Hz, 1H), 6.57 # (td, J=7.6, 1.4 Hz,1H), 4.87 (s, 2H), 4.56 (d, J=6.3 Hz, 2H), 2.61 (s, 3H), 2.56 (s, 3H).MS (m/z): 430.53 (calc) 431.1 (MH+) (found) 6 179 315

4-((4-(1H- pyrazol-5- yl)pyrimidin-2- ylamino)methyl)- N-(2-amino-phenyl)benzamide ¹H NMR (DMSO-d₆) δ (ppm): 13.16 (s, 1H), 9.56 (s, 1H),8.26 (s, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.80 (d, J=14.5 Hz, 2H), 7.47 (s,2H), 7.13 (d, J=7.6 Hz, 1H), 7.08 (s, 0.5H), 6.94 (td, J=7.2, 1.6 Hz,1H), 6.80 (s, 0.5H), 6.74 (dd, J=7.9, 1.6 Hz, 1H), 6.56 # (td, J=6.9,1.4 Hz, 1H), 4.86 (s, 2H), 4.60 (s, 2H). MS (m/z): 385.42 (calc) 386.2(MH+) (found) 6 180 316

N-(2-amino- phenyl)-4- ((4-(2,4- dimethyloxazol-5- yl)pyrimidin-2-ylamino)methyl) benzamide ¹H NMR (DMSO-d₆) δ (ppm): 9.57 (s, 1H), 8.31(d, J=4.5 Hz, 1H), 7.93-7.89 (m, 3H), 7.41 (d, J=8.2 Hz, 2H), 7.12 (d,J=7.6 Hz, 1H), 6.94 (td, J=7.2, 1.6 Hz, 1H), 6.76-6.73 (m, 2H), 6.56(td, J=8.0, 1.2 Hz, 1H), 4.87 (s, 2H), 4.59 (d, J=6.5 # Hz, 2H), 2.44(s, 3H), 2.35 (s, 3H). MS (m/z): 414.46 (calc) 415.3 (MH+) (found) 6 181317

N-(2-amino- phenyl)-4- ((4(3- (hydroxymethyl) isoxazol-5-yl)pyrimidin-2- ylamino)methyl) benzamide ¹H NMR (MeOD-d₄) δ (ppm): 8.42(d, J=5.1 Hz, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.16(d, J=8.4 Hz, 1H), 7.08 (d, J=4.9 Hz, 1H), 7.06-7.04 (m, 2H), 6.89 (d,J=8.0 Hz, 1H), 6.75 (t, J=7.6 Hz, 1H), 4.72 (s, # 2H), 4.69 (s, 2H). MS(m/z): 416.43 (calc) 417.3 (MH+) (found) 59, 6 182 321

N-(2-amino- phenyl)-4-((4(3- (hydroxymethyl)- 5-methylisoxazol-4-yl)pyrimidin-2- ylamino)methyl) benzamide ¹H NMR (DMSO-d₆) δ (ppm):9.54 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 7.94-7.88 (m, 3H), 7.42 (d, J=8.0Hz, 2H), 7.13 (d, J=7.6 Hz, 1H), 6.94 (t, J=7.0 Hz, 2H), 6.75 (d, J=7.8Hz, 1H), 6.57 (t, J=7.4 Hz, 1H), 5.53 (t, J=5.9 # Hz, 1H), 4.87 (s, 2H),4.65-4.59 (m, 4H). (CH₃ singlet is probably overlapped by DMSO signal)¹H NMR (MeOD-d₄) δ (ppm): 8.32 (d, J=5.3 Hz, 1H), 7.92 (d, J=8.2 Hz,2H), 7.48 (d, J=8.2 Hz, 2H), 7.16 (d, J=7.6 Hz, 1H), 7.06 (t, J=7.2 Hz,1H), 6.94 (d, J=5.3 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.76 (t, J=6.3 Hz,1H), 4.72 (s, 2H), 4.70 (s, 2H), 2.61 (s, # 3H). MS (m/z): 430.46 (calc)431.2 (MH+) (found) 60, 6 183 325

N-(2-amino- phenyl)-4- ((4-(1-methyl-1H- 1,2,3-triazol-4-yl)pyrimidin-2- ylamino)methyl) benzamide ¹H NMR (DMSO-d₆) δ (ppm): 9.56(s, 1H), 8.33 (d, J=4.9 Hz, 1H), 8.20 (s, 1H), 7.96 (t, J=6.3 Hz, 1H),7.89 (d, J=8.2 Hz, 2H), 7.47 (s, 2H), 7.12 (d, J=7.8 Hz, 1H), 7.02 (d,J=4.7 Hz, 1H), 6.94 (td, J=7.2, 1.5 Hz, 1H), 6.75 (dd, # J=7.9, 1.3 Hz,1H), 6.57 (td, J=7.9, 1.4 Hz, 1H), 4.86 (s, 2H), 4.60 (d, J=6.3 Hz, 2H),4.22 (s, 3H). MS (m/z): 400.44 (calc) 401.2 (MH+) (found) 61 184 326

N-(2-amino- phenyl)-4- ((4-(3-methyl-3H- 1,2,3-triazol-4-yl)pyrimidin-2- ylamino)methyl) benzamide ¹H NMR (DMSO-d₆) δ (ppm): 9.57(s, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 8.14 (s, 1H), 7.90 (d, J= 8.2 Hz,2H), 7.43 (d, J=8.2 Hz, 2H), 7.13 (d, J=7.2 Hz, 1H), 7.08 (d, J=5.1 Hz,1H), 6.94 (td, J=8.2, 1.6 Hz, 1H), 6.75 (dd, J=7.8, 1.2 # Hz, 1H), 6.57(t, J=8.2 Hz, 1H), 4.87 (s, 2H), 4.62 (d, J=6.3 Hz, 2H), 4.40 (s, 1H),4.12 (s, 2H). MS (m/z): 400.44 (calc) 401.2 (MH+) (found) 61 185 332

N-(2-amino- phenyl)-4- ((4-(2-methylH- imidazo[1,2-a]pyridin-3-yl)pyrimidin-2- ylamino)methyl) benzamide ¹H-NMR, DMSO-d6 δ (ppm): 9.60 (s,1H); 8.97 (bs, 1H); 8.35 (bs, 1H); 8.03 (t, J=6.3 Hz, 1H); 7.94 (d,J=8.2 Hz, 2H); 7.56 (bs, 1H); 7.47 (d, J=8.2 Hz, 2H); 7.33 (bs, 1H);7.13 (d, J=7.3 Hz, 1H); 6.94 (dt, J=1.4, 7.3 Hz, 1H); 6.85 # (d, J=4.3Hz, 1H); 6.75 (dd, J=1.0, 8.0 Hz, 1H); 6.71 (bs, 1H); 6.57 (t, J=7.3 Hz,1H); 4.87 (bs, 2H); 4.62 (d, J=6.1 Hz, 2H); 2.59 (bs, 3H). MS (m/z):449.51 (calc) 450.2 (MH+) (found) 186 334

4-((4-(2-amino-4- methylthiazol-5- yl)pyrimidin-2- ylamino)methyl)-N-(2-amino- phenyl)benzamide ¹H NMR (MeOD-d₄) δ (ppm): 8.16 (d, J=5.9Hz, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.35-7.26 (m,4H), 6.92 (d, J=6.1 Hz, 1H), 4.73 (s, 2H), 2.55 (s, 3H). MS (m/z):431.51 (calc) 432.2 (MH+) (found) 63 187 335

N-(2-amino- phenyl)-4-((4-(5- (2-(dimethyl- amino)aceta mido)-3-methyl-thiophen-2- yl)pyrimidin-2- ylamino)methyl) benzamide ¹H NMR (MeOD-d₄) δ(ppm): 8.23 (d, J=5.3 Hz, 1H), 7.92 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0Hz, 2H), 7.16 (d, J=7.4 Hz, 1H), 7.06 (t, J=7.2 Hz, 1H), 6.89-6.86 (m,2H), 6.75 (t, J=7.6 Hz, 1H), 4.68 (s, # 2H), 3.60 (s, 2H), 2.59 (s, 6H),256 (s, 3H). MS (m/z): 516.62 (calc) 517.3 (MH+) (found) 63 0 188 342

N-(2-amino- phenyl)-4- (4-(pyridin-3- yl)pyrimidin-2- ylamino)benza-mide ¹H NMR (DMSO-d₆) δ (ppm): 10.10 (s, 1H), 9.52 (s, 1H), 9.35 (d,J=1.9 Hz, 1H), 8.73 (dd, J=4.9, 1.8 Hz, 1H), 8.66 (d, J=5.1 Hz, 1H),8.52 (dt, j=8.2, 2.2 Hz, 1H), 7.96 (d, J=2.0 Hz, 4H), 7.61 (d, J=4.9 Hz,1H), 7.59 (d, J=5.1 Hz, 1H), 7.15 (d, J=7.3 # Hz, 1H), 6.95 (td, J=8.0,1.6 Hz, 1H), 6.77 (dd, J=7.8, 1.2 Hz, 1H), 6.59 (td, J=7.4, 1.4 Hz, 1H),4.89 (s, 2H). MS (m/z): 382.42 (calc) 383.3 (MH+) (found) 64

Example 193(S)—N-(2-Aminophenyl)-4-(3-(pyridin-3-ylamino)pyrrolidin-1-yl)benzamide(361) Step 1: N-p-Nosyl-3-pyridine (362)

To a stirred solution of 2-aminopyridine (3.03 g, 32.2 mmol) in THF (15mL) were successively added DCM (30 mL), 4-nitrobenzenesulfonyl chloride(1.50 g, 68.7 mmol), and Et₃N (9.88 mL, 70.9 mmol). The solution turnedorange and a precipitate formed. The suspension was allowed to stir atroom temperature for 1 h, solvents were evaporated under reducedpressure and the solid residue was suspended in methanol (200 mL). Tothe suspension a large excess (>10 eq) of sodium methoxide was added,the mixture was stirred at 50° C. for 3 h, quenched with HCl 1N (2 mL)and concentrated under reduced pressure at 80° C. until the volumebecame 50 mL. The concentrated solution was further acidified with 1NHCl until neutral pH. A precipitate formed which was collected byfiltration to afford the title compound (7.67 g, 85% yield). ¹H NMR(DMSO-d₆) δ (ppm): 10.88 (s, 1H), 8.36 (d, J=9.0 Hz, 2H), 8.28 (dd,J=6.1, 1.4 Hz, 1H), 8.27 (d, J=2.5 Hz, 1H), 7.50 (ddd, J=8.4, 2.7, 1.6Hz, 1H), 7.30 (ddd, J=8.2, 4.7, 0.8 Hz, 1H). m/z: 280.1 (MH⁺).

Step 2: tert-Butyl 4-((R)-3-hydroxypyrrolidin-1-yl)benzoate (363)

To a solution of t-butyl 4-fluorobenzoate (2.17 g, 11.0 mmol) and(R)-(+)-3-pyrrolidinol (1.00 g, 11.5 mmol) in DMSO (8 mL) was addedpotassium carbonate (1.53 g, 11.0 mmol). The mixture was stirred at 130°C. for 18 h and poured into stirring water (100 mL) while still hot. Theresulting beige precipitate was collected by filtration and dried at120° C. for 1.5 h to afford the title compound (2.64 g, 91% yield). ¹HNMR (Acetone-d₆) δ (ppm): 7.78 (d, J=9.0 Hz, 2H), 6.54 (d, J=8.8 Hz,2H), 4.58 (bs, 1H), 4.15 (bs, 1H), 3.55 (dd, J=10.36, 4.7 Hz, 1H), 3.49(t, J=6.8 Hz, 1H), 3.42 (td, J=9.2, 2.3 Hz, 1H), 3.28 (d, J=10.8 Hz,1H), 2.21-2.10 (m, 1H), 2.09-2.03 (m, 1H), 1.56 (s, 9H). m/z: 520.3(MH⁺).

Step 3: tert-Butyl4-((S)-3-N-p-nosyl(pyridin-3-ylamino)pyrrolidin-1-yl)benzoate (364)

To a solution of compound 362 (6.00 g, 21.5 mmol) in THF (100 mL), weresuccessively added carbinol 363 (5.66 g, 21.5 mmol), triphenylphosphine(6.76 g, 25.8 mmol) and diethyl azodicarboxylate (4.06 mL, 25.8 mmol).The mixture was stirred at room temperature for 18 h and the solvent wasremoved in vacuo. The residue was purified by flash chromatography usingEtOAc/Hex (40:60) as an eluent to afford the title compound (4.68 g, 42%yield). ¹H NMR (DMSO-d₆) d(ppm): 8.58 (dd, J=4.7, 1.4 Hz, 1H), 8.48 (d,J=8.0 Hz, 2H), 8.38 (d, J=2.0 Hz, 1H), 8.13 (d, J=9.0, 2H), 7.72 (d,J=9.0 Hz, 2H), 7.61 (ddd, J=8.0, 2.5, 1.6 Hz, 1H), 7.39 (dd, J=8.2, 4.9Hz, 1H), 6.43 (d, J=9.0 Hz, 2H), 5.17 (quint, J=8.2 Hz, 1H), 3.77 (dd,J=10.4, 7.2 Hz, 1H), 3.36 (dd, J=10.4, 6.7 Hz, 1H), 3.26 (dd, J=15.1,7.8 Hz, 1H), 3.06 (td, J=12.3, 3.3 Hz, 1H), 2.43-2.38 (m, 1H), 2.02-1.94(m, 1H), 1.55 (s, 9H). m/z: 525.3 (MH⁺)

Step 4: tert-Butyl 4-((S)-3-(pyridin-3-ylamino)pyrrolidin-1-yl)benzoate(365)

To a solution of the nitro compound 364 (4.68 g, 8.92 mmol) in DMF (45mL), were successively added lithium hydroxide (1.31 g, 31.2 mmol) andthioglycolic acid (930 μL, 13.4 mmol). The mixture was stirred for 3days at room temperature, the solvent was removed in vacuo at 80° C. andthe residue was partitioned between EtOAc and H₂O. Organic layer wascollected and extracted with HCl 1N. Acidic layer was collected andneutralized with a saturated NaHCO₃ solution. A white precipitate wasformed which was extracted with EtOAc. The EtOAc solution was washedwith brine, dried over MgSO4, and concentrated in vacuo to afford thetitle compound (1.65 g, 54% yield) as a white solid. ¹H NMR:(Acetone-d₆) δ(ppm): 8.08 (d, J=2.2 Hz, 1H), 7.86 (d, J=4.3 Hz, 1H),7.79 (d, J=9.0 Hz, 2H), 7.09 (dd, J=8.2, 4.3 Hz, 1H), 7.05 (ddd, J=8.2,2.7, 1.6 Hz, 1H), 6.57 (d, J=8.8 Hz, 2H), 5.54 (d, J=6.5 Hz, 1H), 4.32(sext, J=5.3 Hz, 1H), 3.78 (dd, J=10.2, 5.9 Hz, 1H), 3.56 (dd, J=17.0,7.2 Hz, 1H), 3.47 (td, J=8.0, 5.1 Hz, 1H), 3.31 (dd, J=10.2, 3.9 Hz,1H), 2.44 (sext., J=7.8 Hz, 1H), 2.13 (sext, J=5.1 Hz, 1H), 1.56 (s,9H). m/z: 340.3 (MH⁺).

Step 5.(S)—N-(2-Aminophenyl)-4-(3-(pyridin-3-ylamino)pyrrolidin-1-yl)benzamide(361)

To a suspension of compound 365 (19 mg, 0.56 mmol) in DCM 500 μL wasadded trifluoroacetic acid (200 μL). The solution was refluxed at 50° C.for 3 h and concentrated in vacuo to produce a white solid. Thismaterial was dissolved in DMF (500 μL) and was treated with Et₃N (16 μL,0.118 mmol) and BOP (30 mg, 0.067 mmol). The reaction mixture wasstirred for 10 min. and 1,2-henylenediamine (7 mg, 0.061 mmol) andanother portion of Et₃N (23 μL, 0.168 mmol) were added. The mixture wasstirred for 2 h at room temperature and DMF was removed in vacuo at 80°C. The residue was partitioned between EtOAc and H₂O. The organic layerwas collected and extracted with 1N HCl and neutralized with sat.NaHCO₃. A precipitate formed which was extracted with EtOAc, dried overMgSO₄, and concentrated in vacuo. The residue was purified by flashchromatography using MeOH/CHCl₃ (7:93) as the eluent to afford the titlecompound (11 mg, 52% yield). ¹H NMR: (CD₃OD) δ(ppm): 7.97 (d, J=2.7 Hz,1H), 7.86 (d, J=8.8 Hz, 2H), 7.78 (dd, J=4.7, 1.0 Hz, 1H), 7.18-7.10 (m,3H), 7.05 (td, J=7.4, 0.6 Hz, 1H), 6.89 (dd, J=7.8, 1.2 Hz, 1H), 6.76(td, J=7.4, 1.4 Hz, 1H), 6.64 (d, J=8.8 Hz, 2H), 4.25 (quint, J=4.9 Hz,1H), 3.77 (dd, J=10.2, 6.1 Hz, 1H), 3.57 (dd, J=17.0, 7.0 Hz, 1H), 3.49(td, J=8.0, 5.3 Hz, 1H), 3.29 (q, J=6.7 Hz, 1H), 2.41 (sext, J=7.2 Hz,1H), 2.10 (sext, J=4.9 Hz, 1H). m/z: 372.4 (MH⁺).

Example 194(R)—N-(2-Aminophenyl)-4-(3-(pyridin-3-ylamino)pyrrolidin-1-yl)benzamide(366)

The title compound was obtained following the same procedures describedin scheme 69, example 193 but substituting (R)-(+)-3-pyrrolidinol for(S)-(−)-3-pyrrolidinol. (108 mg, 21% yield) ¹H NMR: (DMSO-d₆) δ(ppm):9.34 (s, 1H), 8.00 (d, J=2.3 Hz, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.77 (dd,J=4.7, 1.2 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 7.08 (dd, J=8.0, 4.5 Hz,1H), 6.99-6.97 (m, 1H), 6.92 (t, J=7.8 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H),6.60-6.56 (m, 3H), 6.17 (d, J=6.8 Hz, 1H), 4.81 (s, 2H), 4.19-4.17 (m,1H), 3.71 (dd, J=10.2, 6.5 Hz, 1H), 3.53-3.47 (m, 1H), 3.42-3.38 (m,1H), 3.18 (dd, J=10.4, 4.1 Hz, 1H), 2.32 (sext, J=6.3 Hz, 1H), 1.99(sext, J=4.7 Hz, 1H). m/z: 374.2 (MH⁺).

Example 195(S)—N-(2-Aminophenyl)-4-(3-(pyridin-3-yloxy)pyrrolidin-1-yl)benzamide(367)

The title compound was obtained following the same procedures describedin scheme 69, example 193 but skipping steps 1 and 4 and substitutingcompound 362 for 3-hydroxypyridine (24 mg, 44% yield) ¹H NMR:(Acetone-d₆) δ(ppm): 8.88 (s, 1H), 8.31 (d, J=2.9 Hz, 1H), 8.19 (d,J=4.7 Hz, 1H), 7.93 (d, J=8.8 Hz, 2H), 7.41 (ddd, J=8.4, 2.9, 1.4 Hz,1H), 7.31 (ddd, J=8.4, 4.5, 0.6 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 6.97(td, J=7.8, 1.4 Hz, 1H), 6.85 (dd, J=8.0, 1.4 Hz, 1H), 6.66 (d, J=9.0Hz, 2H), 6.65 (td, J=8.0, 1.4 Hz, 1H), 5.34-5.32 (m, 1H), 4.62 (s, 2H),3.84 (dd, J=11.3, 4.7 Hz, 1H), 3.61-3.56 (m, 3H), 2.50-2.34 (m, 2H).m/z: 375.2 (MH⁺).

Example 196(R)—N-(2-Aminophenyl)-4-(3-(pyridin-3-yloxy)pyrrolidin-1-yl)benzamide(368)

The title compound was obtained following the same procedures describedin scheme 69, example 193 skipping steps 1 and 4 and substitutingcompound 362 for 3-hydroxypyridine and (R)-(+)-3-pyrrolidinol for(S)-(−)-3-pyrrolidinol. (14 mg, 12% yield) ¹H NMR: (Acetone-d₆) δ(ppm):8.85 (s, 1H), 8.31 (d, J=2.9 Hz, 1H), 8.19 (dd, J=4.5, 1.2 Hz, 1H), 7.93(d, J=8.8 Hz, 2H), 7.42 (ddd, J=8.4, 2.9, 1.4 Hz, 1H), 7.31 (ddd, J=8.4,4.7, 0.8 Hz, 1H), 7.26 (d, J=7.8, 1.6 Hz, 1H), 6.97 (td, J=7.2, 1.6 Hz,1H), 6.85 (dd, J=7.8, 1.2 Hz, 1H), 6.68 (d, J=8.8 Hz, 6.66 (td, J=7.6,1.4 Hz, 1H), 3.56-5.33 (m, 1H), 4.60 (bs, 2H), 3.86 (dd, J=11.3, 4.7 Hz,1H), 3.62-3.57 (m, 3H), 2.50-2.35 (m, 2H). m/z: 375.2 (MH⁺).

Example 197(S)—N-(2-Aminophenyl)-4-(3-(phenylamino)pyrrolidin-1-yl)benzamide (369)

The title compound was obtained following the same procedures describedin scheme 69, example 193 but substituting compound 3-aminopyridine foraniline. (7 mg, 16% yield) ¹H NMR: (Acetone-d₆) δ(ppm): 8.84 (s, 1H),7.91 (d, J=8.8 Hz, 2H), 7.25 (dd, J=7.8, 1.2 Hz, 1H), 7.12 (t, J=7.2 Hz,2H), 6.96 (dt, J=8.0, 1.4 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.71 (dd,J=8.8, 1.0 Hz, 2H), 6.66 (t, J=7.8 Hz, 1H), 6.62 (d, J=8.8 Hz, 2H), 5.26(d, J=7.6 Hz, 1H), 4.60 (bs, 1H), 4.30 (quint, J=5.3 Hz, 1H), 3.79 (dd,J=10.0 Hz, 1H), 3.57 (q, J=9.6 Hz, 1H), 3.50-3.45 (m, 1H), 3.30 (dd,J=10.2, 3.9 Hz, 1H), 2.42 (sext, J=6.8 Hz, 1H). m/z: 373.1 (MH⁺).

Example 198(R)—N-(2-Aminophenyl)-4-(3-(phenylamino)pyrrolidin-1-yl)benzamide (370)

The title compound was obtained following the same procedures describedin scheme 69, example 193 but substituting 3-aminopyridine for anilineand (R)-(+)-3-pyrrolidinol for (S)-3-pyrrolidinol. (22 mg, 23% yield) ¹HNMR (CDCl₃) δ 7.79 (m, 2H), 7.2-7.4 (m, 2H), 7.05 (s, 1H), 6.8 (m, 3H)6.65 (m, 2H), 6.53(m, 2H), 4.24 (br.s., 1H), 3.9(m, 2H), 3.73 (m, 1H),3.26 (m, 1H), 2.37 (m, 1H), 2.09 (m, 1H) m/z: 373.3 (MH⁺).

Example 199 (S)—N-(2-Aminophenyl)-4-(3-phenoxypyrrolidin-1-yl)benzamide(371)

The title compound was obtained following the same procedures describedin scheme 69, example 193 but skipping steps 1 and 4 and substitutingcompound 362 for phenol. (50 mg, 33% yield) ¹H NMR (CDCl₃) δ 7.79 (μ,3H), 7.3 (m, 3H), 7.03 (m, 1H), 6.96 (m, 1H), 6.90 (d, 2H, J=8.8 Hz),6.80 (m, 2H), 6.54 (d, J=8.8 Hz, 2H), 5.08 (br.s., 1H), 3.71 (dd, J=4.7Hz, J=11.0 Hz, 1H), 3.6 (m, 3H), 2.41 (m, 1H), 2.31 (m, 1H) m/z: 374.2(MH⁺).

Example 200(S)-Methyl-4-(1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yloxy)benzoate(372)

The title compound was obtained following the same procedures describedin scheme 69, example 193 but skipping steps 1 and 4 and substitutingcompound 362 for methyl 4-hydroxybenzoate. (143 mg, 42% yield) ¹H NMR(CDCl₃) δ 8.0 (m, 2H), 7.81 (m, 2H), 7.72 (s, 1H), 7.25 (m, 1H), 7.06(m, 1H), 6.91(m, 2H), 6.84 (m, 2H), 6.59 (m, 2H), 5.16 (br.s., 1H),3.9(s, 3H), 3.78 (m, 1H), 3.60 (m, 3H), 2.4 (m, 2H) m/z: 432.4 (MH⁺).

Example 201 (S)-4-(1-(4-(2-Aminophenylcarbamoyl)phenyl)pyrrolidin-3-yloxy)benzoic acid (373)

A solution of 372 (100 mg, 0.23 mmol) and KOH (100 mg, 1.78 mmol) in1:1:1 mixture of THF/water/MeOH (6 mL) was stirred at room temperaturefor 5 days. The reaction mixture was concentrated and partitionedbetween water (5 mL) and ether (5 mL). Organic phase was discarded andthe aqueous phase was acidified to pH=6 using 1M HCl solution andextracted with EtOAc. The extract was dried over Na₂SO4, filtered andconcentrated. The residue was purified by flash chromatography, eluentMeOH-DCM (gradient of MeOH from 5 till 20% MeOH) to afford the titlecompound (20 mg, 21% yield). ¹H NMR (DMSO) δ 9.34 (σ, 1H), 7.85 (m, 4H),7.11 (d, 1H, J=7.8 Hz), 7.00 (d, J=8.4 Hz, 2H), 6.92 (d, 2H, J=7.7 Hz),6.75 (d, J=8.0 Hz, 2H), 6.6 (m, 3H), 5.26 (br.s., 1H), 3.75 (m, 1H),[3.34 DMSO, 4H], 2.44 (m, 1H), 2.31 (m, 1H) m/z: 418.4 (MH⁺).

Example 202(S)—N-(2-Aminophenyl)-4-(3-(3,4,5-trimethoxyphenoxy)pyrrolidin-1-yl)benzamide(374)

The title compound was obtained following the same procedures describedin scheme 69, example 193 but skipping steps 1 and 4 and substitutingcompound 362 for 3,4,5-trimethoxyphenol. (30 mg, 21%) ¹H NMR (CDCl₃) δ7.79 (d, 2H, J=8.8 Hz), 7.73 (s, 1H), 7.26 (d, 1H, J=7.4 Hz), 7.05 (t,J=7.7 Hz, 1H), 6.81 (d, 2H, J=7.7 Hz), 6.57 (d, J=8.7 Hz, 2H), 6.14 (s,2H), 5.04 (br.s., 1H), 3.88 (s, 6H), 3.80 (s, 3H), 3.71 (dd, J=4.7 Hz,J=11.0 Hz, 1H), 3.6 (m, 3H), 2.41 (m, 1H), 2.31 (m, 1H) m/z: 464.4(MH⁺).

Example 203(S)—N-(2-Aminophenyl)-4-(3-(benzo[d][1,3]dioxol-5-yloxy)pyrrolidin-1-yl)benzamide(375)

The title compound was obtained following the same procedures describedin scheme 69, example 193 but skipping steps 1 and 4 and substitutingcompound 362 for benzo[d][1,3]dioxol-5-ol. (31 mg, 15%) ¹H NMR (CDCl₃) δ8.95 (s, 1H), 7.87 (d, 2H, J=8.0 Hz), 7.80 (d, J=8.7 Hz, 1H), 7.67 (s,1H), 7.48 (s, 0.5H) 7.04 (m, 1H), 6.83(m, 1H), 6.71 (m, 1H), 6.57 (d,2H), 6.48 (s, 1H), 6.33 (m, 1H), 5.93 (s, 2H), 4.96 (br.s., 1H), 3.67(m,1H), 3.57 (m, 3H), 2.36 (m, 1H), 2.26 (m, 1H) m/z: 418.2 (MH⁺).

Example 204(S)—N-(2-Aminophenyl)-4-(3-(4-phenoxyphenoxy)pyrrolidin-1-yl)benzamide(376)

The title compound was obtained following the same procedures describedin scheme 69, example 193 but skipping steps 1 and 4 and substitutingcompound 362 for 4-phenoxyphenol. ¹H NMR (CDCl₃) δ 7.81 (m, 2H), 7.70(s, 1H), 7.67 (s, 0.5H), 7.2-7.4 (m, 4H) 6.8-7.2 (m, 10H), 6.6(m, 2H),5.05 (br.s., 1H), 3.6(m, 1H), 3.5 (m, 3H), 2.41 (m, 1H), 2.32 (m, 1H)m/z: 466.4 (MH⁺).

Example 205(S)—N-(2-Aminophenyl)-4-(3-(4-nitrophenoxy)pyrrolidin-1-yl)benzamide(377)

The title compound was obtained following the same procedures describedin scheme 69, example 193 but skipping steps 1 and 4 and substitutingcompound 362 for 4-nitrophenol. (12 mg, 6%) ¹H NMR (CDCl₃) δ 8.12 (d,2H, J=9.1 Hz), 7.72 (d, J=8.8 Hz, 2H), 7.18 (d, J=7.3 Hz, 1H), 6.97 (t,1H, J=7.7 Hz), 6.87 (d, J=9.1 Hz, 2H), 6.50 (d, 2H, J=8.6 Hz), 5.09(br.s., 1H), 3.71 (dd, J=4.5 Hz, J=11.3 Hz, 1H), 3.6 (m, 3H2.3 (m, 2H)m/z: 419.1 (MH⁺).

Example 206(S)—N-(2-Aminophenyl)-4-(3-(pyridin-2-ylthio)pyrrolidin-1-yl)benzamide(378)

The title compound was obtained following the same procedures describedin scheme 69, example 193 but skipping steps 1 and 4 and substitutingcompound 362 for pyridine-2-thiol. (22 mg, 28%) ¹H NMR (CDCl₃) δ 8.44(μ, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.69 (s, 1H), 7.49 (t, 1H, J=7.4 Hz),7.27 (m, 1H), 7.18 (d, 1H, J=8.0 Hz), 7.0-7.1 (m, 2H), 6.82 (d, 7.8 Hz,2H), 6.55 (d, J=9.0 Hz, 2H), 4.55 (m, 1H), 3.9-4.0 (m, 3H), 3.4-3.6 (m,4H) 2.6 (m, 1H), 2.2 (m, 1H) m/z: 391.0 (MH⁺). TABLE 13 Characterizationof examples 193-206 prepared according to the scheme 69.

Ex. Cpd Ar Y Name Characterization 193 361

NH (S)-N-(2-aminophenyl)-4-(3- (pyridin-3-ylamino)pyrrolidin-1-yl)benzamide ¹H NMR: (CD₃OD) δ (ppm): 7.97 (d, J=2.7 Hz, 1H), 7.86 (d,J=8.8 Hz, 2H), 7.78 (dd, J=4.7, 1.0 Hz, 1H), 7.18-7.10 (m, 3H), 7.05(td, J=7.4, 0.6 Hz, 1H), 6.89 (dd, J=7.8, 1.2 Hz, 1H), 6.76 (td, J=7.4,1.4 Hz, 1H), 6.64 (d, J=8.8 Hz, 2H), 4.25 (quint, J=4.9 Hz, 1H), 3.77(dd, J=10.2, # 6.1 Hz, 1H), 3.57 (dd, J=17.0, 7.0 Hz, 1H), 3.49 (td,J=8.0, 5.3 Hz, 1H), 3.29 (q, J=6.7 Hz, 1H), 2.41 (sext, J=7.2 Hz, 1H),2.10 (sext, J=4.9 Hz, 1H). 194 366

NH (R)-N-(2-aminophenyl)-4-(3- (pyridin-3-ylamino)pyrrolidin-1-yl)benzamide ¹H NMR: (DMSO-d₆) δ (ppm): 9.34 (s, 1H), 8.00 (d, J=2.3 Hz,1H), 7.84 (d, J=8.8 Hz, 2H), 7.77 (dd, J=4.7, 1.2 Hz, 1H), 7.12 (d,J=7.6 Hz, 1H), 7.08 (dd, J=8.0, 4.5 Hz, 1H), 6.99-6.97 (m, 1H), 6.92 (t,J=7.8 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.60-6.56 (m, 3H), 6.17 (d, J=6.8Hz, 1H), # 4.81 (s, 2H), 4.19-4.17 (m, 1H), 3.71 (dd, J=10.2, 6.5 Hz,1H), 3.53-3.47 (m, 1H), 3.42-3.38 (m, 1H), 3.18 (dd, J=10.4, 4.1 Hz,1H), 2.32 (sext, J=6.3 Hz, 1H), 1.99 (sext, J=4.7 Hz, 1H). 195 367

O (S)-N-(2-aminophenyl)-4-(3- (pyridin-3-yloxy)pyrrolidin-1-yl)benzamide ¹H NMR: (Acetone-d₆) δ (ppm): 8.88 (s, 1H), 8.31 (d, J=2.9Hz, 1H), 8.19 (d, J=4.7 Hz, 1H), 7.93 (d, J=8.8 Hz, 2H), 7.41 (ddd,J=8.4, 2.9, 1.4 Hz, 1H), 7.31 (ddd, J=8.4, 4.5, 0.6 Hz, 1H), 7.26 (d,J=7.8 Hz, 1H), 6.97 (td, J=7.8, 1.4 Hz, 1H), 6.85 (dd, J=8.0, 1.4 Hz,1H), 6.66 (d, J=9.0 # Hz, 2H), 6.65 td, J=8.0, 1.4 Hz, 1H), 5.34-5.32(m, 1H), 4.62 (s, 2H), 3.84 (dd, J=11.3, 4.7 Hz, 1H), 3.61-3.56 (m, 3H),2.50-2.34 (m, 2H). 196 368

O (R)-N-(2-aminophenyl)-4-(3- (pyridin-3-yloxy)pyrrolidin-1-yl)benzamide ¹H NMR: (Acetone-d₆) δ (ppm): 8.85 (s, 1H), 8.31 (d, J=2.9Hz, 1H), 8.19 (dd, J=4.5, 1.2 Hz, 1H), 7.93 (d, J=8.8 Hz, 2H), 7.42(ddd, J=8.4, 2.9, 1.4 Hz, 1H), 7.31 (ddd, J=8.4, 4.7, 0.8 Hz, 1H), 7.26(d, J=7.8, 1.6 Hz, 1H), 6.97 (td, J=7.2, 1.6 Hz, 1H), 6.85 (dd, J=7.8,1.2 Hz, 1H), # 6.68 (d, J=8.8 Hz, 6.66 (td, J=7.6, 1.4 Hz, 1H),3.56-5.33 (m, 1H), 4.60 (bs, 2H), 3.86 (dd, J=11.3, 4.7 Hz, 1H),3.62-3.57 (m, 3H), 2.50-2.35 (m, 2H). 197 369

NH (S)-N-(2-aminophenyl)-4-(3- (phenylamino)pyrrolidin-1- yl)benzamide¹H NMR: (Acetone-d₆) δ (ppm): 8.84 (s, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.25(dd, J=7.8, 1.2 Hz, 1H), 7.12 (t, J=7.2 Hz, 2H), 6.96 (dt, J=8.0, 1.4Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.71 (dd, J=8.8, 1.0 Hz, 2H), 6.66 (t,J=7.8 Hz, 1H), 6.62 (d, J=8.8 Hz, 2H), 5.26 (d, J=7.6 Hz, 1H), 4.60 (bs,# 1H), 4.30 (quint, J=5.3 Hz, 1H), 3.79 (dd, J=10.0 Hz, 1H), 3.57 (q,J=9.6 Hz, 1H), 3.50-3.45 (m, 1H), 3.30 (dd, J=10.2, 3.9 Hz, 1H), 2.42(sext, J=6.8 Hz, 1H). 198 370

NH (R)-N-(2-aminophenyl)-4-(3- (phenylamino)pyrrolidin-1- yl)benzamide¹H NMR (CDCl₃) δ (ppm) 7.79 (m, 2H), 7.2-7.4 (m, 2H), 7.05 (s, 1H), 6.8(m, 3H) 6.65 (m, 2H), 6.53 (m, 2H), 4.24 (br.s., 1H), 3.9 (m, 2H), 3.73(m, 1H), 3.26 (m, 1H), 2.37 (m, 1H), 2.09 (m, 1H) 199 371

O (S)-N-(2-aminophenyl)-4-(3- phenoxypyrrolidin-1-yl)benzamide ¹H NMR(CDCl₃) δ (ppm) 7.79 (m, 3H), 7.3 (m, 3H), 7.03 (m, 1H), 6.96 (m, 1H),6.90 (d, 2H, J=8.8 Hz), 6.80 (m, 2H), 6.54 (d, J=8.8 Hz, 2H), 5.08(br.s., 1H), 3.71 (dd, J=4.7 Hz, J=11.0 Hz, 1H), 3.6 (m, 3H), 2.41 (m,1H), 2.31 (m, 1H) 200 372

O (S)-methyl-4-(1-(4-(2-aminophenyl carbamoyl)phenyl)pyrrolidin-3-yloxy)benzoate ¹H NMR (CDCl₃) δ (ppm): 8.0 (m, 2H), 7.81 (m, 2H), 7.72(s, 1H), 7.25 (m, 1H), 7.06 (m, 1H), 6.91 (m, 2H), 6.84 (m, 2H), 6.59(m, 2H), 5.16 (br.s., 1H), 3.9 (s, 3H), 3.78 (m, 1H), 3.60 (m, 3H), 2.4(m, 2H) 201 373

O (S)-4-(1-(4-(2-aminophenyl carbamoyl)phenyl)pyrrolidin-3-yloxy)benzoic acid ¹H NMR: (DMSO-d₆) δ (ppm): 9.34 (s, 1H), 7.85 (m,4H), 7.11 (d, 1H, J=7.8 Hz), 7.00 (d, J=8.4 Hz, 2H), 6.92 (d, 2H, J=7.7Hz), 6.75 (d, J=8.0 Hz, 2H), 6.6 (m, 3H), 5.26 (br.s., 1H), 3.75 (m,1H), [3.34 DMSO, 4H], 2.44 (m, 1H), 2.31 (m, 1H) 202 374

O (S)-N-(2-aminophenyl)-4-(3-(3,4,5- trimethoxyphenoxy)pyrrolidin-1-yl)benzamide ¹H NMR (CDCl₃) δ (ppm) 7.79 (d, 2H), J=8.8 Hz), 7.73 (s,1H), 7.26 (d, 1H, J=7.4 Hz), 7.05 (t, J=7.7 Hz, 1H), 6.81 (d, 2H, J=7.7Hz), 6.57 (d, J=8.7 Hz, 2H), 6.14 (s, 2H), 5.04 (br.s., 1H), 3.88 (s,6H), 3.80 (s, 3H), 3.71 (dd, J=4.7 Hz, J=11.0 Hz, 1H), 3.6 (m, 3H), 2.41(m, 1H), # 2.31 (m, 1H) 203 375

O (S)-N-(2-aminophenyl)-4-(3- (benzo[d][1,3]dioxol-5-yloxy)pyrrolidin-1-yl)benzamide ¹H NMR (CDCl₃) δ (ppm) 8.95 (s, 1H),7.87 (d, 2H, J=8.0 Hz), 7.80 (d, J=8.7 Hz, 1H), 7.67 (s, 1H), 7.48 (s,.5H) 7.04 (m, 1H), 6.83 (m, 1H), 6.71 (m, 1H), 6.57 (d, 2H), 6.48 (s,1H), 6.33 (m, 1H), 5.93 (s, 2H), 4.96 (br.s., 1H), 3.67 (m, 1H), 3.57(m, 3H), 2.36 (m, 1H), 2.26 (m, 1H) 204 376

O (S)-N-(2-aminophenyl)-4-(3-(4- phenoxyphenoxy)pyrrolidin-1-yl)benzamide ¹H NMR (CDCl₃) δ (ppm) 7.81 (m, 2H), 7.70 (s, 1H), 7.67 (s,.5H), 7.2-7.4 (m, 4H) 6.8-7.2 (m, 10H), 6.6 (m, 2H), 5.05 (br.s., 1H),3.6 (m, 1H), 3.5 (m, 3H), 2.41 (m, 1H), 2.32 (m, 1H) 205 377

O (S)-N-(2-aminophenyl)-4-(3-(4- nitrophenoxy)pyrrolidin-1- yl)benzamide¹H NMR (CDCl₃) δ (ppm) 8.12 (d, 2H, J=9.1 Hz), 7.72 (d, J=8.8 Hz, 2H),7.18 (d, J=7.3 Hz, 1H), 6.97 (t, 1H, J=7.7 Hz), 6.87 (d, J=9.1 Hz, 2H),6.50 (d, 2H, J=8.6 Hz), 5.09 (br.s., 1H), 3.71 (dd, J=4.5 Hz, J=11.3 Hz,1H), 3.6 (m, 3H 2.3 (m, 2H) 206 378

S (S)-N-(2-aminophenyl)-4-(3- (pyridin-2-ylthio)pyrrolidin-1-yl)benzamide ¹H NMR (CDCl₃) δ (ppm) 8.44 (m, 1H), 7.78 (d, J=8.8 Hz,2H), 7.69 (s, 1H), 7.49 (t, 1H, J=7.4 Hz), 7.27 (m, 1H), 7.18 (d, 1H,J=8.0 Hz), 7.0-7.1 (m, 2H), 6.82 (d, 7.8 Hz, 2H), 6.55 (d, J=9.0 Hz,2H), 4.55 (m, 1H), 3.9-4.0 (m, 3H), 3.4-3.6 (m, 4H) 2.6 (m, 1H), 2.2 (m,1H)

Example 207N-(2-Aminophenyl)-5-((4-(pyridin-2-yl)pyrimidin-2-ylamino)methyl)thiophene-2-carboxamide(379) Step 1. tert-Butyl2-(5-formylthiophene-2-carboxamido)phenylcarbamate (380)

A solution of 5-formylthiophene-2-carboxylic acid (350 mg, 2.24 mmol),tert-butyl 2-aminophenylcarbamate (467 mg, 2.24 mmol) and triethylamine(470 μL, 340 mg, 3.36 mmol) and BOP (1.1 g, 2.68 mmol) in DMF (10 mL)was stirred at room temperature for 2 hours. The reaction mixture wasconcentrated and purified by flash chromatography using 25% EtOAc inhexanes as an eluent, yielding 260 mg (33%) of the title compound. ¹HNMR (CDCl3)

9.95 (s, 1H), 9.7 (br. s, 1H), 7.84 (d, 1H, J=8.0 Hz), 7.74 (m, 2H),7.15 (m, 2H), 6.72 (s, 1H), 1.56 (s, 9H). LRMS: (calc) 346.1; (found)369.1 (M+Na)

Step 2. tert-Butyl2-(5-((4-(pyridin-2-yl)pyrimidin-2-ylamino)methyl)thiophene-2-carboxamido)phenylcarbamate(381)

A solution of aldehyde 380 (260 mg, 0.75 mmol),4-(pyridin-3-yl)pyrimidin-2-amine (85 mg, 0.5 mmol) and acetic acid (100μL) in DCE (2 mL) was treated with NaBH(OAc)₃ (22 mg, 1 mmol) and theresultant mixture was stirred at room temperature overnight. It was thenquenched by addition of saturated NaHCO₃ (5 mL) and the aqueous phasewas extracted with EtOAc. Organic extract was dried with Na₂SO₄,filtered and concentrated to provide a crude product which was purifiedby flash chromatography using 80-20% mixture EtOAc-hexane as an eluent,to afford the title compound (35 mg, 14% yield). LRMS: (calc) 502.2;(found) 503.4 (M+H¹)

N-(2-Aminophenyl)-5-((4-(pyridin-2-yl)pyrimidin-2-ylamino)methyl)thiophene-2-carboxamide(379)

A solution of 381 (35 mg, 0.07 mmol) in 1:1 mixture of DCM and TFA (4mL) was stirred at room temperature for 30 minutes. The reaction mixturewas concentrated to produce a solid which was triturated with ether toafford the title compound as a TFA salt (26 mg, 75% yield). ¹H NMR(MeOH-d4)

9.31 (s, 1H), 8.68 (s, 1H), 8.66 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 7.77(d, J=3.9 Hz, 1H), 7.68 (m, 1H), 7.1-7.5 (m, 6H). LRMS: (calc) 402.2;(found) 403.3 (M+H¹).

Example 208N-(2-Aminophenyl)-4-((3-(6-methoxypyridin-3-yl)-1H-pyrazol-5-ylamino)methyl)benzamide(382) Step 1: 3-(6-Methoxypyridin-3-yl)-1H-pyrazol-5-amine (383)

MeCN (940 μL, 736 mg, 17.96 mmol) in THF (20 mL) was treated with 2.5 Msolution of BuLi in hexanes (7.2 mL, 17.96 mmol) at −78° C. and thereaction mixture was allowed to stir at the same temperature for 30 min,treated with a solution of methyl 6-methoxynicotinate (2 g, 11.96 mmol)in THF (10 mL) at −78° C. and was stirred at room temperature foradditional 2 hours. It was then quenched by addition of water (10 mL)and 1M solution of HCl (10 mL). The resultant mixture was concentratedin vacuo, the residue was mixed with hydrazine monohydrate (5 mL) inEtOH (30 mL), refluxed for 2 hours, cooled and concentrated underreduced pressure produce a solid which was purified by flashchromatography using 10% MeOH in DCM as an eluent, to afford the titlecompound (720 mg, 32% yield). ¹H NMR (MeOH-d4)

8.39 (s, 1H), 7.89 (d, J=8.6 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 5.85 (s,1H), 3.91 (s, 3H). LRMS: (calc) 190.1; (found) 191.1 (M+H¹).

Step 2: Methyl4-((3-(6-methoxypyridin-3-yl)-1H-pyrazol-5-ylamino)methyl)benzoate (384)

A solution of amine 383 (720 mg, 3.79 mmol), methyl 4-formylbenzoate(745 mg, 4.54 mmol), and Bu₂SnCl₂ (230 mg, 0.76 mmol) in dry THF (5 mL)was stirred at room temperature for 2 hours. It was then treated withPhSiH₃ (514 μL, 451 mg, 4.17 mmol) and allowed to stir for another hourat room temperature. The reaction mixture was quenched by addition ofMeOH and vigorous stirring for 45 min. It was then concentrated in vacuoand the residue was purified by flash chromatography using the gradient50-100% EtOAc in hexane to afford the title compound (672 mg, 52%yield). LRMS: (calc) 338.1; (found) 339.2 (M+H¹)

Step 3:4-((3-(6-Methoxypyridin-3-yl)-1H-pyrazol-5-ylamino)methyl)benzoic acid(385)

A solution of 384 (672 mg, 1.99 mmol) and KOH (300 mg, 5.35 mmol) in1:1:1 mixture of THF, MeOH and water (9 mL) was stirred at roomtemperature overnight. The reaction mixture was acidified to pH=4 byaddition of 1M HCl and concentrated in vacuo. The residue was trituratedwith water and the solid was collected by filtration and dried to affordthe title compound (640 mg, 99% yield). LRMS: (calc) 324.1; (found)325.2 (M+H¹)

Step 4:N-(2-Aminophenyl)-4-((3-(6-methoxypyridin-3-yl)-1H-pyrazol-5-ylamino)methyl)benzamide(382)

A solution of 385 (640 mg, 1.97 mmol) in MeCN (10 mL) was sequentiallytreated with Et₃N (831 μL, 603 mg, 5.96 mmol), EDC (571 mg, 2.98 mmol),HOBT (334 mg, 2.18 mmol) and 1,2-phenylene diamine (429 mg, 3.97 mmol)and allowed to stir overnight. The reaction mixture was concentrated andpartitioned between DCM (15 mL) and saturated NH₄Cl (15 mL). The organicphase was collected, dried with Na₂SO₄, filtered and concentrated. Theresultant solid was purified by flash chromatography using the gradient3-15% MeOH in DCM to afford the title compound (113 mg, 14% yield). ¹HNMR (DMSO-d₆)

9.65 (s, 1H), 8.43 (s, 1H), 7.92 (m, 3H), 7.48 (d, J=8.0 Hz, 2H), 7.16(d, J=7.4 Hz, 1H), 6.97 (t, J=7.6 Hz, 1H), 6.81 (t, J=8.2 Hz, 2H), 6.63(t, J=7.4 Hz, 1H), 5.85 (s, 1H), 4.34 (s, 2H), 3.85 (s, 3H). LRMS:(calc) 414.2; (found) 415.3 (M+H¹)

Example 209N-(2-aminophenyl)-4-((3-(pyridin-3-yl)-1H-pyrazol-5-ylamino)methyl)benzamide(386)

Title compound was prepared according to the scheme 71 (example 208)starting from methyl nicotinate. ¹H NMR (MeOH-d4)

8.80 (s, 1H), 8.43 (d, J=3.9 Hz, 1H), 8.04 (m, 2H), 7.94 (d, J=8.2 Hz,2H), 7.53 (d, J=8.2 Hz, 1H), 7.43 (m, 1H), 7.15 (d, J=7.6 Hz, 1H), 7.05(t, J=7.2 Hz, 2H), 6.88 (d, J=8.0 Hz, 1H), 6.75 (t, J=7.4 Hz, 1H), 5.94(s, 1H), 4.45 (s, 2H). LRMS: (calc) 384.2; (found) 385.2 (M+H¹)

Example 210N-(2-Aminophenyl)-4-((3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-5-ylamino)methyl)benzamide(387)

Title compound was prepared according to the scheme 71 (example 208)starting from methyl 3,4,5-trimethoxybenzoate. ¹H NMR (MeOH-d4)

7.92 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.16 (d, J=7.9 Hz, 1H),7.06 (t, J=7.8 Hz, 1H), 6.93 (s, 2H), 6.88 (d, J=8.0 Hz, 1H), 6.75 (t,J=7.6 Hz, 1H), 5.89 (s, 1H), 4.45 (s, 2H), 3.87 (s, 6H), 3.77 (s, 3H).LRMS: (calc) 473.3; (found) 474.4 (M+H¹)

Example 211N-(2-Aminophenyl)-4-((4-chloro-3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-5-ylamino)methyl)benzamide(388)

Steps 1, 2 and 3.4-((3-(3,4,5-Trimethoxyphenyl)-1H-pyrazol-5-ylamino)methyl)benzoic acid(389)

Title compound was obtained according to the scheme 71, steps 1, 2 and 3using in the first step methyl 3,4,5-trimethoxybenzoate instead ofmethyl 6-methoxynicotinate. LRMS: (calc) 383.1; (found) 384.2 (M+H¹).

Step 4:N-(2-Aminophenyl)-4-((4-chloro-3-(3,4,5-trimethoxyphenyl)-1H-pyrazol-5-ylamino)methyl)benzamide(388)

A solution of 389 (30 mg, 0.08 mmol) in a 1:1 mixture of DCM and SOCl2(2 mL) was stirred at room temperature for 30 min. The reaction mixturewas concentrated and treated with a solution of 1,2-phenylene diamine(18 mg, 0.16 mmol) in THF (2 mL) and stirred at room temperature for 15min, concentrated under reduced pressure to produce a solid which waspurified by preparative HPLC (column AQUASIL C-18; 5 μM; 230×21.2 mm;eluent 30-95% MeOH in water) to afford the title compound (8 mg, 20%yield). ¹H NMR (MeOH-d4)

7.92 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.17 (d, J=7.6 Hz, 1H),7.06 (m, 3H), 6.89 (d, J=7.8 Hz, 1H), 6.75 (t, J=7.2 Hz, 1H), 4.55 (s,2H), 3.89 (s, 6H), 3.80 (s, 3H). LRMS: (calc) 507.2; (found) 508.3(M+H¹).

Example 212N-(2-Aminophenyl)-4-((8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)methyl)benzamide(389) Step 1. tert-Butyl 2-(4-(Boc-aminomethyl)benzamido)phenylcarbamate(391)

A solution of 4-((tert-butoxycarbonylamino)methyl)benzoic acid (1 g,3.98 mmol) in DMF (10 mL) was treated sequentially with EDC (930 mg,4.84 mmol), HOBT (682 mg, 4.46 mmol) and Et₃N (670 μL, 489 mg, 4.84mmol) at room temperature and allowed to stir overnight. The reactionmixture was concentrated under reduced pressure and partitioned betweenchloroform (10 mL) and water (10 mL). Organic phase was collected,washed with 1M HCl (10 mL) and saturated NaHCO₃ (10 mL), dried, filteredand evaporated to form a residue which was purified by flashchromatography using 30% EtOAc in hexanes as an eluent to afford thetitle compound (840 mg, 51%). LRMS: (calc) 441.2; (found) 442.2 (M+H¹)

Step 2. 4-(Aminomethyl)-N-(2-aminophenyl)benzamide (392)

A solution of 391 (840 mg, 1.9 mmol) in 2:1 mixture of DCM/TFA (6 mL)was stirred at room temperature for 2 hours. The reaction mixture wasconcentrated in vacuo to afford the title compound as a mixture of themono and di-TFA salt. (1.33 g, 100% yield). LRMS: (calc) 241.2; (found)242.2 (M+H¹).

Step 3.N-(2-Aminophenyl)-4-((8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)methyl)benzamide(390)

A solution of sulfoxide 393 (Barvian, M. et al. J. Med. Chem. (2001)44(6); 1016-1016) (166 mg, 0.74 mmol), bis-amine 392 (535 mg, 2.23 mmol)and triethylamine (620 μL, 4.46 mmol) in DME (3 mL) was stirred at roomtemperature for 3 hours. The reaction mixture was concentrated andpartitioned between EtOAc (5 mL) and water (5 mL). Organic phase wascollected and washed successively with saturated solutions of NH₄Cl (5mL) and NaHCO₃ (5 mL), dried over Mg₂SO₄, filtered and concentrated toproduce a residue which was triturated with 1:1 EtOAc/hexane solution toafford the title compound (48 mg, 16% yield). ¹H NMR (CDCl₃)

3.62 (s, 3H), 4.80 (m, 2H), 6.42 (d, J=10 Hz, 1H), 6.85 (d, J=8 Hz, 2H),7.10 (m, 1H), 7.30 (m, 1H), 7.50 (m, 2H), 7.87 (s, 1H), 7.897 (m, 2H),8.43 (s, 1H). LRMS: (calc) 400.0; (found) 401.0 (M+H¹)

Example 213N-(2-Aminophenyl)-4-((7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-ylamino)methyl)benzamide(394)

Title compound was prepared in a similar manner as the example 212(scheme 72) starting from the sulfoxide 395 obtained by literatureprocedure similarly to the sulfoxide 393. ¹H NMR (DMSO)

4.60 (s, 2H), 4.90 (s, 2H), 6.10 (d, J=10 Hz, 1H), 6.55 (t, J=7 Hz, 2H),6.75 (m, 1H), 6.90 (t, J=7 Hz, 2H), 7.10 (m, 2H), 7.40 (m, 2H), 7.65 (m,1H), 7.90 (m, 1H), 8.55 (s, 1H), 9.69 (s, 1H). LRMS: (calc) 386.0;(found) 387.0 (M+H¹).

Example 214 (S)—N-(1-(4-(2-Aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl)nicotinamide (396) Step 1.(S)-tert-Butyl 4-(3-aminopyrrolidin-1-yl)benzoate (397)

Title compound was obtained similarly to the aminoester 363 using thesame procedure as described in step 2, scheme 69. ¹H NMR (CDCl₃) δ 7.83(d, J=8.8 Hz, 1H), 6.46 (d, J=8.8 Hz, 1H), 3.75 (m, 1H), 3.35-3.6 (m,3H), 3.06 (dd, J=4.7 Hz, J=9.8 Hz, 1H), 2.26 (m, 1H), 1.85 (m, 1H), 1.57(s, 9H), LRMS: (calc) 262.1; (found) 263.0 (M+H¹).

Step 2. (S)-tert-Butyl 4-(3-(nicotinamido)pyrrolidin-1-yl)benzoate (398)

A solution of 397 (100 mg, 0.38 mmol), Et₃N (160 μL, 1.14 mmol) andnicotinoyl chloride HCl salt (68 mg, 0.38 mmol) in DCM (2 mL) wasstirred at room temperature for 1 hour and quenched by adding saturatedNH₄Cl sat solution (5 mL). The organic phase was separated, dried overNa₂SO₄, filtered and concentrated to produce a residue which waspurified by flash chromatography using 5% MeOH in DCM as an eluent toafford the title compound (110 mg, 79% yield). LRMS: (calc) 367.2;(found). 368.1 (M+H¹).

Step 3. (S)-4-(3-(Nicotinamido)pyrrolidin-1-yl)benzoic acid (399)

The title compound was obtained as the mixture of monosalt and disaltsimilarly to the compound 117 using the same procedure as described instep 5, scheme 28. LRMS: (calc) 311.1; (found) 312.1 (M+H¹).

Step 4.(S)—N-(1-(4-(2-Aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl)nicotinamide(396)

A solution of 399 (93 mg, 0.3 mmol), phenylene diamine (65 mg, 0.6mmol), EDC (86 mg, 0.45 mmol), HOBT (53 mg, 0.33 mmol) and Et₃N (125 μL,91 mg, 0.9 mmol) in acetonitrile (2 mL) was stirred at room temperatureovernight. The reaction mixture was concentrated and the residue waspurified by flash chromatography using the gradient 5-20% MeOH in DCM asan eluent to afford the title compound (24 mg, 16% yield). ¹H NMR(CDCl₃) δ 8.97 (s, 1H), 8.66 (d, J=4.9 Hz, 1H), 8.21 (d, J=3.9 Hz, 1H),7.87 (d, 2H, J=8.8 Hz), 7.52 (dd, J=5.1 Hz, J=8.0 Hz, 1H), 7.15 (d, 1H,J=7.9 Hz), 7.05 (t, J=8.1 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.76 (t,J=7.3 Hz, 1H), 6.66 (d, J=9.0 Hz, 2H), 4.78 (m, 1H), 3.80 (dd, J=6.7 Hz,J=10.2 Hz, 1H), 3.61 (m, 1H), 3.49 (m, 1H), 3.41 (m, 1H), 2.4 (m, 1H),2.2 (m, 1H). LRMS: (calc) 401.2; (found) 402.2 (M+H¹).

Example 215N-(2-Aminophenyl)-4-((S)-3-((S)-pyridin-2-ylsulfinyl)pyrrolidin-1-yl)benzamide(400)

A solution of 378 (15 mg, 0.04 mmol) and mCPBA (6 mg, 0.04 mmol) in DCM(2 mL) was stirred at room temperature for 1 hour. The reaction mixturewas concentrated and the residue was purified by flash chromatographyusing the gradient EtOAc to 5% MeOH in DCM as an eluent, to afford thetitle compound (13 mg, 80% yield). ¹H NMR (CDCl₃) δ ¹H NMR (CDCl₃) δ8.63 (m, 1H), 8.58 (m, 1H), 7.6-8.0 (m, 10H), 7.40 (m, 2H), 7.25 (m,1H), 7.05 (m, 2H), 6.85 (m, 3H), 6.58 (d, J=8.8 Hz, 2H), 6.50 (d, J=11.1Hz, 2H), 3.7-4.0 (m, 6H), 3.2-3.5 (m, 4H), 2.4-2.8 (m, 3H), 2.95 (m,1H). LRMS: (calc) 406.1; (found) 407.1 (M+H¹).

Assay Example 1 Inhibition of Histone Deacetylase Enzymatic Activity

1. Human HDAC-1

Assay 1. HDAC inhibitors were screened against a cloned recombinanthuman HDAC-1 enzyme expressed and purified from a Baculovirus insectcell expression system. For deacetylase assays, 20,000 cpm of the[³H]-metabolically labeled acetylated histone substrate (M. Yoshida etal., J. Biol. Chem. 265(28): 17174-17179 (1990)) was incubated with 30μg of the cloned recombinant hHDAC-1 for 10 minutes at 37° C. Thereaction was stopped by adding acetic acid (0.04 M, final concentration)and HCl (250 mM, final concentration). The mixture was extracted withethyl acetate and the released [³H]-acetic acid was quantified byscintillation counting. For inhibition studies, the enzyme waspreincubated with compounds at 4° C. for 30 minutes prior to initiationof the enzymatic assay. IC₅₀ values for HDAC enzyme inhibitors weredetermined by performing dose response curves with individual compoundsand determining the concentration of inhibitor producing fifty percentof the maximal inhibition.

Assay 2. The following protocol was also used to assay the compounds ofthe invention. In the assay, the buffer used was 25 mM HEPES, pH 8.0,137 mM NaCl, 2.7 mM KCl, 1 mM MgCl₂ and the substrate wasBoc-Lys(Ac)-AMC in a 50 mM stock solution in DMSO. The enzyme stocksolution was 4.08 μg/mL in buffer. The compounds were pre-incubated (2μl in DMSO diluted to 13 μl in buffer for transfer to assay plate) withenzyme (20 μl of 4.08 μg/ml) for 10 minutes at room temperature (35 μlpre-incubation volume). The mixture was pre-incubated for 5 minutes atroom temperature. The reaction was started by bringing the temperatureto 37° C. and adding 16 μl substrate. Total reaction volume was 50 μl.The reaction was stopped after 20 minutes by addition of 50 μldeveloper, prepared as directed by Biomol (Fluor-de-Lys developer, Cat.# KI-105). A plate was incubated in the dark for 10 minutes at roomtemperature before reading (λ_(Ex)=360 nm, λ_(Em)=470 nm, Cutoff filterat 435 nm).

IC₅₀ values for representative compounds are presented in Table 14.Assay 1 was used to measure HDAC activity of compounds 10c, 13e, 16d,26b, 44, 47, 61a, 61b, 63, 134, 138, and 308. Assay 2 was used tomeasure HDAC activity of compounds 361, 366, 367, 368, 369, 370, 371,372, 373, 374, 375, 376, 377, and 378. In Table 14, “a” indicatesactivity of ≦0.1 μM, “b” indicates activity of ≦1 μM, “c” indicatesactivity of ≦5 μM, and “d” indicates activity of >5 μm. For the H4-AcT24 EC vs. MS-275 assay in Table 14, “u” indicates less than 1, “v”indicates 1, and “w” indicates greater than 1. For the H3 Ac t24 assayin Table 14, “x” indicates activity of ≦1 μM, “y” indicates activity of≦10 μM, and “z” indicates activity of ≦20 μM.

2. MTT Assay

HCT116 cells (2000/well) were plated into 96-well tissue culture platesone day before compound treatment. Compounds at various concentrationswere added to the cells. The cells were incubated for 72 hours at 37° C.in 5% CO₂ incubator. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5diphenyltetrazolium bromide, Sigma) was added at a final concentration of 0.5mg/ml and incubated with the cells for 4 hours before one volume ofsolubilization buffer (50% N,N-dimethylformamide, 20% SDS, pH 4.7) wasadded onto the cultured cells. After overnight incubation, solubilizeddye was quantified by colorimetric reading at 570 nM using a referenceat 630 nM using an MR700 plate reader (Dynatech Laboratories Inc.). ODvalues were converted to cell numbers according to a standard growthcurve of the relevant cell line. The concentration which reduces cellnumbers to 50% of that of solvent treated cells is determined as MTTIC₅₀. IC₅₀ values for representative compounds are presented in Table14. In Table 14, “a” indicates activity of ≦0.1 μM, “b” indicatesactivity of ≦1 μM, and “c” indicates activity of ≦5 μM.

3. Histone H4 Acetylation in Whole Cells by Immunoblots

T24 human bladder cancer cells growing in culture were incubated withHDAC inhibitors for 16 h. Histones were extracted from the cells afterthe culture period as described by M. Yoshida et al. (J. Biol. Chem.265(28): 17174-17179 (1990)). 20 g of total histone protein was loadedonto SDS/PAGE and transferred to nitrocellulose membranes. Membraneswere probed with polyclonal antibodies specific for acetylated histoneH-4 (Upstate Biotech Inc.), followed by horse radish peroxidaseconjugated secondary antibodies (Sigma). Enhanced Chemiluminescence(ECL) (Amersham) detection was performed using Kodak films (EastmanKodak). Acetylated H-4 signal was quantified by densitometry.Representative data are presented in Table 14. Data are presented as theratio of the concentration effective for reducing the acetylated H-4signal by 50% (EC₅₀) using the indicated compound of the invention to acontrol compound, MS-275. If the indicated ratio is 1, then the compoundof the invention is as effective as the MS-275 control compound. If theratio is less than 1, then the compound of the invention is moreeffective than the MS-275 control compound. Further informationregarding the MS-275 compound can be found in Suzuki et al., J. Med.Chem. 1999, pp. 3001-3003.

MS-275

4. Histone H3 Acetylation Assay

T24 human bladder cancer cells growing in culture are incubated withHDAC inhibitors for 16 h. Cell viability is determined by adding 10 μlAlamar Blue (BioSource, DAL1100). Cells are washed once with PBS andfixed with methanol precooled to −20° C. for 10 min. The cells are thenwashed twice in PBS. The fixed cells are blocked with 50 μl of PBS+0.1%Triton X-100. Cells are probed with rabbit-anti-acetyl-H3 (Upstate#06-599) as the primary antibody and then with goat-anti-rabbit-HRP(Sigma #A-0545) as the secondary antibody. Fluorescence is read byfluorometer at Ex:550, Em:610, Cutoff:590 (Auto PMT, 15 reads/well)after addition of Amplex-Red. Fluorescence signal is normalized againstcell viability derived from Alamar Blue. Data is presented in Table 14as EC₅₀. Maximum acetylation signal of MS-275 (fluorescence unit) ismeasured as E_(max). The concentration of compound which gives 50% ofE_(max) is EC₅₀. In Table 14, “x” indicates activity of ≦1 μM, “y”indicates activity of ≦10 μM, and “z” indicates activity of ≦20 μM.TABLE 14 In vitro profile of selected HDAC inhibitors. MTT Ex- HDAC-1HCT116 H4-Ac T24 am- IC₅₀ IC₅₀ EC vs. MS- ple Compd Structure (μM) (μM)275 4  10c

c b v 16  13e

c b v 20  16d

b b v 30  26b

c a v 42  44

c a v 43  47

c b u 48  61a

c a v 49  61b

c a u 51  63

c b v 72 134

c b u 76 138

c a u 173 308

c b w HDAC1 IC₅₀ MTT HCT116 H3 Ac Example Comp Structure μM IC₅₀ t24(μM) 193 361

a b y 194 366

b c z 195 367

b b y 196 368

b b 197 369

b b x 198 370

c c 199 371

b b 220 372

a b 201 373

b d 202 374

a b x 203 375

a d x 204 376

c c 205 377

b b 206 378

b b y

Assay Example 2 Antineoplastic Effects of Histone Deacetylase Inhibitorson Human Tumor Xenografts In Vivo

Eight to ten week old female BCD1 mice (Taconic Labs, Great Barrington,N.Y.) were injected subcutaneously in the flank area with 2×10⁶preconditioned HCT116 human colorectal carcinoma cells, SW48 coloncancer cells, and A549 lung cancer cells. Preconditioning of these cellswas done by a minimum of three consecutive tumor transplantations in thesame strain of nude mice. Subsequently, tumor fragments of approximately30 mgs were excised and implanted subcutaneously in mice, in the leftflank area, under Forene anesthesia (Abbott Labs, Geneva, Switzerland).When the tumors reached a mean volume of 100 mm³, the mice were treatedintraperitoneally by daily injection, with a solution of the histonedeacetylase inhibitor in DMSO, at a starting dose of 10 mg/kg. Theoptimal dose of the HDAC inhibitor was established by dose responseexperiments according to standard protocols. Tumor volume was calculatedevery second day post infusion according to standard methods (e.g.,Meyer et al., Int. J. Cancer 43: 851-856 (1989)). Treatment with theHDAC inhibitors according to the invention caused a significantreduction in tumor weight and volume relative to controls treated withvehicle only (i.e., no HDAC inhibitor).

Assay Example 3

Combined Antineoplastic Effect of Histone Deacetylase Inhibitors andHistone Deacetylase Antisense Oligonucleotides on Tumor Cells In Vivo

The purpose of this example is to illustrate the ability of the combineduse of a histone deacetylase inhibitor of the invention and a histonedeacetylase antisense oligonucleotide to enhance inhibition of tumorgrowth in a mammal. Preferably, the antisense oligonucleotide and theHDAC inhibitor inhibit the expression and activity of the same histonedeacetylase.

Mice bearing implanted HCT116 tumors (mean volume 100 mm³) are treateddaily with saline preparations containing from about 0.1 mg to about 30mg per kg body weight of histone deacetylase antisense oligonucleotide.A second group of mice is treated daily with pharmaceutically acceptablepreparations containing from about 0.01 mg to about 5 mg per kg bodyweight of HDAC inhibitor.

Some mice receive both the antisense oligonucleotide and the HDACinhibitor. Of these mice, one group may receive the antisenseoligonucleotide and the HDAC inhibitor simultaneously intravenously viathe tail vein. Another group may receive the antisense oligonucleotidevia the tail vein, and the HDAC inhibitor subcutaneously. Yet anothergroup may receive both the antisense oligonucleotide and the HDACinhibitor subcutaneously. Control groups of mice are similarlyestablished which receive no treatment (e.g., saline only), a mismatchantisense oligonucleotide only, a control compound that does not inhibithistone deacetylase activity, and a mismatch antisense oligonucleotidewith a control compound.

Tumor volume is measured with calipers. Treatment with the antisenseoligonucleotide plus the histone deacetylase protein inhibitorsaccording to the invention causes a significant reduction in tumorweight and volume relative to controls. TABLE 12 % Inhibition (relativeto vehicle control No. of Com- Exam- Dose animals pound ple mg/kg Routeentered HCT116 SW48 A549  10a 2 30 ip 6 16.1 23.0 —  26b 30 40 ip 6 —75.1 74.4  26c 32 30 ip 6 88.0 89.5 —  29a 34 30 ip 6 — 70.2 31.8  31b37 30 ip 6 39.4 47.8 —  34a 39 30 ip 6 — 25.5 67.1  58b 47 30 ip 6 29.434.6 — 138 76 30 ip 6 79.8 — 83.7 158 82 30 ip 6 — 43.2 42.6 194 93 30ip 6 54.5 23.1 —  212f 104 30 ip 6 65.7 32.7 —  212h 106 30 ip 6 — 44.054.4 252 133 30 ip 6 70.6 25.9 — 296 161 30 ip 6 63.9 53.4 —

position Accession Nucleotide within Oligo Target Number PositionSequence Gene HDAC1 AS1 Human HDAC1 U50079 1585-16045′-GAAACGTGAGGGACTCAGCA-3′ 3′-UTR (SEQ ID NO:1) HDAC1 AS2 Human HDAC1U50079 1565-1584 5′-GGAAGCCAGAGCTGGAGAGG-3′ 3′-UTR (SEQ ID NO:2) HDAC1MM Human HDAC1 U50079 1585-1604 5′-GTTAGGTGAGGCACTGAGGA-3′ 3′-UTR (SEQID NO:3) HDAC2 AS Human HDAC2 U31814 1643-16225′-GCTGAGCTGTTCTGATTTGG-3′ 3′-UTR (SEQ ID NO:4) HDAC2 MM Human HDAC2U31814 1643-1622 5′-CGTGAGCACTTCTCATTTCC-3′ 3′-UTR (SEQ ID NO:5) HDAC3AS Human HDAC3 AF039703 1276-1295 5′-CGCTTTCCTTGTCATTGACA-3′ 3′-UTR (SEQID NO:6) HDAC3 MM Human HDAC3 AF039703 1276-12955′-GCCTTTCCTACTCATTGTGT-3′ 3′-UTR (SEQ ID NO:7) HDAC4 AS1 Human HDAC4AB006626  514-33 5′-GCTGCCTGCCGTGCCCACCC-3′ 5′-UTR (SEQ ID NO:8) HDAC4MM1 Human HDAC4 AB006626  514-33 5′-CGTGCCTGCGCTGCCCACGG-3′ 5′-UTR (SEQID NO:9) HDAC4 AS2 Human HDAC4 AB006626 7710-295′-TACAGTCCATGCAACCTCCA-3′ 3′-UTR (SEQ ID NO:10) HDAC4 MM4 Human HDAC4AB006626 7710-29 5′-ATCAGTCCAACCAACCTCGT-3′ 3′-UTR (SEQ ID NO:11) HDAC5AS Human HDAC5 AF039691 2663-2682 5′-CTTCGGTCTCACCTGCTTGG-3′ 3′-UTR (SEQID NO:12) HDAC6 AS Human HDAC6 AJ011972 3791-38105′-CAGGCTGGAATGAGCTACAG-3′ 3′-UTR (SEQ ID NO:13) HDAC6 MM Human HDAC6AJ011972 3791-3810 5′-GACGCTGCAATCAGGTAGAC-3′ 3′-UTR (SEQ ID NO:14)HDAC7 AS Human HDAC7 AF239243 2896-2915 5′-CTTCAGCCAGGATGCCCACA-3′3′-UTR (SEQ ID NO:15) HDAC8 AS1 Human HDAC8 AF230097   51-705′-CTCCGGCTCCTCCATCTTCC-3′ 5′-UTR (SEQ ID NO:16) HDAC8 AS2 Human HDAC8AF230097 1328-1347 5′-AGCCAGCTGCCACTTGATGC-3′ 3′-UTR (SEQ ID NO:17)

1. A compound of formula (1):

or a pharmaceutically acceptable salt thereof, wherein Cy is aryl,heteroaryl, cycloalkyl, or heterocyclyl, each of which is optionallysubstituted and each of which is optionally fused to one or more aryl orheteroaryl rings, or to one or more saturated or partially unsaturatedcycloalkyl or heterocyclic rings, each of which rings is optionallysubstituted; X is selected from the group consisting of a chemical bond,L, W-L, L-W, and L-W-L, wherein W, at each occurrence, is S, O, C═O, orN(R⁹), where R⁹ is selected from the group consisting of hydrogen,alkyl, hydroxyalkyl, and t-butoxycarbonyl; and L, at each occurrence, isindependently C₁-C₄ alkylene; Ar is arylene or heteroarylene, each ofwhich is optionally substituted; q is 0 or 1; and T is NH₂ or OH,provided that when Cy is naphthyl, X is —CH₂—, Ar is phenyl, and q is 0or 1, T is not OH.
 2. A compound according to claim 1 wherein q is 1,and T is NH₂.
 3. A compound according to claim 2 wherein Ar isphenylene, and Cy-X— is


4. A compound according to claim 1 wherein q is
 0. 5. A compoundaccording to claim 4, of the formula (1a)

wherein W is S, O, or N(R₉), wherein R₉ is hydrogen or alkyl; and R₈ isH or C₁-C₄ alkyl.
 6. A compound according to claim 5 wherein Cy isselected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,thiazolyl, benzothiazolyl, benzoimidazolyl, and benzotriazolyl, each ofwhich is optionally substituted.
 7. A compound according to claim 5 ofthe formula 1a-1:

wherein W is NH or S; P, Q, M, G and U are independently CH or N,provided that no more than two of P, Q, M, G and U are N and in the ringcontaining P, Q, M, G, and U, an annular S or O is not adjacent toanother annular S or O; R₈ is H or C₁-C₄ alkyl; and groups A and B arethe same or different and are independently selected from H, halogen,C₁-C₄ alkyl, optionally substituted alkoxy including aminoalkoxy,haloalkoxy and heteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro,alkylthio, acylamino, carbamoyl,


8. A compound according to claim 5 of the formula 1a-2:

wherein W is S or NH; R₈ is H or C₁-C₄ alkyl; and groups A and B are thesame or different and are independently selected from H, halogen, C₁-C₄alkyl, optionally substituted alkoxy including aminoalkoxy, haloalkoxyand heteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio,acylamino, carbamoyl,


9. A compound according to claim 5 of the formula 1a-3:

and pharmaceutically acceptable salts thereof wherein W is S or NH, andgroups A and B are the same or different and are independently selectedfrom Hu halogen, C₁-C₄ alkyl, optionally substituted alkoxy includingaminoalkoxy, haloalkoxy and heteroarylalkoxy, alkoxyalkyl, haloalkyl,amino, nitro, alkylthio, acylamino, carbamoyl,


10. A compound according to claim 9 wherein W is NH.
 11. A compoundaccording to claim 5 of the formula 1a-4:

wherein W is S or NH; D is N—R₁₀ or S, E is N or C-A; R₈ and R₁₀ areindependently H or C₁-C₄ alkyl; and groups A and B are the same ordifferent and are independently selected from H, halogen, C₁-C₄ alkyl,optionally substituted alkoxy including aminoalkoxy, haloalkoxy andheteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio,acylamino, carbamoyl,


12. A compound according to claim 11 wherein W is NH.
 13. A compoundaccording to claim 7 of the formula 1a-5:


14. A compound according to claim 13 wherein W is NH.
 15. A compoundaccording to claim 5 wherein W is NH and Cy is quinoxalinyl,phthalimidyl, or benzodioxolyl, each of which is optionally substitutedwith A and/or B, wherein groups A and B are the same or different andare independently selected from H, halogen, C₁-C₄ alkyl, optionallysubstituted alkoxy including aminoalkoxy, haloalkoxy andheteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio,acylamino, carbamoyl,


16. A compound according to claim 1, of the formula (1b):

(1b) wherein X is L, W-L, or L-W, wherein W, at each occurrence, is S,O, or NH; and L is —CH₂—; Y is N or CH; and Z is A, S. NH or CH₂.
 17. Acompound according to claim 16 wherein T is NH₂.
 18. A compoundaccording to claim 16 wherein X is —S—CH₂—, —NH—CH₂— or —CH₂—NH—.
 19. Acompound according to claim 16 wherein Cy is aryl or heteroaryl, each ofwhich is optionally substituted.
 20. A compound according to claim 16wherein Cy is phenyl, pyridyl, pyrimidinyl, or benzothiazolyl, each ofwhich is optionally substituted.
 21. A compound according to claim 16wherein Cy is substituted with A and/or B, wherein groups A and B arethe same or different and are independently selected from H, halogen,C₁-C₄ alkyl, optionally substituted alkoxy including aminoalkoxy,haloalkoxy and heteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro,alkylthio, acylamino, carbamoyl,


22. A compound according to claim 16 wherein Cy is optionallysubstituted with one, two or three groups independently selected fromalkoxy, acyl, morpholino, and phenyl optionally substituted with alkoxy.23. A compound according to claim 1 of the formula (1c):

X is L, W-L, or L-W, wherein W, at each occurrence, is S, O, or NH; andL is —CH₂—; Y is N or CH; and Z is O, S. NH or CH₂.
 24. A compoundaccording to claim 23 wherein T is NH₂.
 25. A compound according toclaim 23 wherein X is —S—CH₂—, —NH—CH₂— or —CH₂—NH—.
 26. A compoundaccording to claim 23 wherein Cy is aryl or heteroaryl, each of which isoptionally substituted.
 27. A compound according to claim 23 wherein Cyis phenyl, pyridyl, pyrimidinyl, or benzothiazolyl, each of which isoptionally substituted.
 28. A compound according to claim 23 wherein Cyis substituted with A and/or B, wherein groups A and B are the same ordifferent and are independently selected from H, halogen, C₁-C₄ alkyl,optionally substituted alkoxy including aminoalkoxy, haloalkoxy andheteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio,acylamino, carbamoyl,


29. A compound according to claim 23 wherein Cy is optionallysubstituted with one two or three groups independently selected fromalkoxy, haloalkoxy, acyl, morpholino, or phenyl optionally substitutedwith alkoxy.
 30. A compound according to claim 1, of the formula (1d):


31. A compound according to claim 30 wherein T is NH₂.
 32. A compoundaccording to claim 30 wherein Cy is:


33. A compound according to claim 1, of the formula (1e):


34. A compound according to claim 33 wherein T is NH₂.
 35. A compoundaccording to claim 33 wherein Cy is heterocyclyl or heteroaryl, each ofwhich is optionally substituted, and each of which contains at least onenitrogen atom as part of the ring.
 36. A compound according to claim 34wherein Cy is optionally substituted with one or two substituentsindependently selected from A and B, wherein groups A and B are the sameor different and are independently selected from H, halogen, C₁-C₄alkyl, optionally substituted alkoxy including aminoalkoxy, haloalkoxyand heteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio,acylamino, carbamoyl,


37. A compound according to claim 33 wherein Cy is optionallysubstituted with one or two substituents independently selected from:—CN,


38. A compound according to claim 4 wherein Ar is phenylene, indolyl orindolinyl, each of which is optionally substituted, and X is absent,CH₂, —O—CH₂—, —S—CH₂—, —S—C(CH₃)(H)—, or —N(R₉)—CH₂.
 39. A compoundaccording to claim 38 wherein Ar is an indolyl or indolinyl group, X isCH₂ or —N(R₉)—CH₂—, and Cy is:


40. A compound according to claim 38 wherein Ar is phenylene, X is—S—CH₂—, or —S—C(CH₃)(H)—, and Cy is:

wherein Y is selected from:


41. A compound according to claim 1, of the formula (1f):


42. A compound according to claim 41 wherein Cy is heterocyclyl orheteroaryl, each of which is optionally substituted, and each of whichcontains at least one nitrogen atom as part of the ring.
 43. A compoundaccording to claim 42 wherein Cy is bound to the phenyl through anitrogen atom.
 44. A compound according to claim 41 wherein Cy is:


45. A compound according to claim 41 of the formula (1f-1):

wherein A is selected from H, halogen, C₁-C₄ alkyl, optionallysubstituted alkoxy including aminoalkoxy, haloalkoxy andheteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio,acylamino, carbamoyl,


46. A compound according to claim 45 wherein T is NH₂.
 47. A compoundaccording to claim 38 wherein Ar is phenylene, X is —O—CH₂—, and Cy is:


48. A compound according to claim 1 of the formula (1 g):

wherein Cy is aryl, or heteroaryl, cycloalkyl, or heterocyclyl, each ofwhich is optionally substituted and each of which is optionally fused toone or more aryl or heteroaryl rings, or to one or more saturated orpartially unsaturated cycloalkyl or heterocyclic rings, each of whichrings is optionally substituted; X is L, W-L, or L-W, wherein W, at eachoccurrence, is S, O, or NH; and L is —CH₂—; T is NH₂ or OH.
 49. Acompound according to claim 48 wherein Cy is optionally substitutedheteroaryl.
 50. A compound according to claim 48 wherein Cy isoptionally substituted pyrimidinyl.
 51. A compound according to claim 48wherein X is —NH—CH₂—.
 52. A compound according to claim 48 wherein T isNH₂.
 53. A compound according to claim 1 of the formula (1 h):

where W is S, O, or NH and groups A and B are the same or different andare independently selected from H, halogen, C₁-C₄ alkyl, optionallysubstituted alkoxy including aminoalkoxy, haloalkoxy andheteroarylalkoxy, alkoxyalkyl, haloalkyl, amino, nitro, alkylthio,acylamino, carbamoyl,


54. A compound according to claim 53 wherein W is NH.
 55. A compoundaccording to claim 53 wherein A is optionally substituted pyridyl oroptionally substituted phenyl.
 56. A compound according to claim 53wherein B is H or halo.
 57. A compound according to claim 1 of theformula (1i):

where W is S, O, or NH and R₄₀ is H or C₁-C₆ alkyl.
 58. A compoundaccording to claim 57 wherein W is NH.
 59. A compound according to claim57 wherein R₄₀ is H.
 60. A compound according to claim 57 wherein R₄₀ ismethyl.